bluuebunny/crossref_metadata_2025 huggingface dataset:
Simultaneous Phenotypically Distinct but Clonally Identical Mucosa-Associated Lymphoid Tissue and Follicular Lymphoma in a Patient With Sjögren’s Syndrome
Authors: Aiello Antonella , Du Ming-Qing , Diss Tim C. , Peng Huai-Zheng , Pezzella Francesco , Papini Daniela , Giardini Roberto , Pilotti Silvana , Pan Lang-Xing , Isaacson Peter G.
Published: October 2019

A 44-year-old woman with a 12-year history of Sjögren’s syndrome (SS) developed a low-grade mucosa-associated lymphoid tissue (MALT) lymphoma in the parotid gland. Two years later, she presented with generalized lymphadenopathy and hepatosplenomegaly and a follicular lymphoma was diagnosed. To investigate the relationship of the two histologically distinct lymphomas, we re-examined their histology and immunophenotype and studied the lymphomatous tissue from the parotid, cervical lymph node, and spleen using molecular genetic methods. Histologic and immunophenotypic studies confirmed the previous diagnoses and also identified a previously unnoticed focus of follicular lymphoma in the second parotid gland biopsy. Polymerase chain reaction (PCR) amplification of the rearranged Ig heavy-chain gene showed the same sized dominant product in the MALT lymphoma and the follicular lymphoma. Similarly, PCR analysis of the t(14:18) translocation yielded an identical sized band from both MALT and follicular lymphoma. Cloning and sequencing of the Ig PCR products showed an identical CDR3 sequence from each lesion, indicating a common clonal lineage. The follicular lymphoma of the parotid gland lymph node and the follicular lymphoma of the spleen showed an identical mutation signature to that of the salivary gland MALT lymphoma. We propose that follicular lymphoma in the parotid gland lymph node may have resulted from colonization of lymphoid follicles by MALT lymphoma cells, following which the tumor cells were induced to express a follicular lymphoma phenotype, due to Bcl-2 overexpression caused by t(14;18), leading to a change in clinical behavior resulting in rapid widespread dissemination of disease. These observations suggest that the distinct phenotypes of low-grade B-cell lymphomas may be the consequence of interplay between genetic and local microenvironmental factors.
In Vivo Marking of Rhesus Monkey Lymphocytes by Adeno-Associated Viral Vectors: Direct Comparison With Retroviral Vectors
Authors: Hanazono Yutaka , Brown Kevin E. , Handa Atsushi , Metzger Mark E. , Heim Dominik , Kurtzman Gary J. , Donahue Robert E. , Dunbar Cynthia E.
Published: October 2019

We have compared adeno-associated virus (AAV)-based and retrovirus-based vectors for their ability to transduce primary T lymphocytes in vitro and then tracked the persistence of these genetically marked lymphocytes in vivo, using the rhesus monkey model. To avoid the complication of immune rejection of lymphocytes transduced with xenogeneic genes in tracking studies primarily designed to investigate transduction efficiency and in vivo kinetics, the vectors were designed without expressed genes. All vectors contained identically mutated β-galactosidase gene (β-gal) and neomycin resistance gene (neo) DNA sequences separated by different length polylinkers, allowing simple differentiation by polymerase chain reaction (PCR). Each of 2 aliquots of peripheral blood lymphocytes from 4 rhesus monkeys were transduced with either AAV or retroviral vectors. The in vitro transduction efficiency (mean vector copy number/cell) after the ex vivo culture was estimated by PCR at 0.015 to 3.0 for AAV, varying depending on the multiplicity of infection (MOI) used for transduction, and 0.13 to 0.19 for the retroviral transductions. Seven days after transduction, Southern blot analysis of AAV-transduced lymphocytes showed double-stranded and head-to-tail concatemer forms but failed to show integration of the AAV vector. AAV and retroviral aliquots were reinfused concurrently into each animal. Although the retrovirally marked lymphocytes could be detected for much longer after infusion, AAV transduction resulted in higher short-term in vivo marking efficiency compared with retroviral vectors, suggesting possible clinical applications of AAV vectors in lymphocyte gene therapy when long-term vector persistence is not required or desired.
PTPROt: An Alternatively Spliced and Developmentally Regulated B-Lymphoid Phosphatase That Promotes G0/G1 Arrest
Authors: Aguiar Ricardo C.T. , Yakushijin Yoshihiro , Kharbanda Samir , Tiwari Sanjay , Freeman Gordon J. , Shipp Margaret A.
Published: October 2019

Protein tyrosine phosphatases (PTP) regulate the proliferation, differentiation, and viability of lymphocytes by modulating their signaling pathways. By using the differential display assay, we have cloned a putative receptor-type PTP, which is predominantly expressed in B-lymphoid tissues (lymph nodes and spleen). This PTP, termed PTPROt (truncated), is a tissue-specific alternatively-spliced form of a human epithelial PTP, PTPRO (PTPU2/GLEPP1). Whereas the epithelial PTPRO includes an ≈800-amino acid extracellular domain, the major (3 kb) PTPROt cDNA predicts a unique 5′ untranslated region and truncated (8 amino acids) extracellular domain with a conserved transmembrane region and single catalytic domain. PTPROt cDNAs encode functional ∼47-kD and ∼43-kD PTPs, which are most abundant in normal naive quiescent B cells and decreased or absent in germinal center B cells and germinal center-derived diffuse large B-cell lymphomas. Because PTPROt was predominantly expressed in naive quiescent B cells, the enzyme’s effects on cell-cycle progression were examined. When multiple stable PTPROt sense, antisense, and vector only B-cell transfectants were grown in reduced serum and synchronized with nocodazole, PTPROt sense clones exhibited markedly increased G0/G1 arrest. Taken together, these data implicate PTPROt in the growth control of specific B-cell subpopulations.
p15INK4BCpG Island Methylation in Primary Acute Leukemia Is Heterogeneous and Suggests Density as a Critical Factor for Transcriptional Silencing
Authors: Cameron Elizabeth E. , Baylin Stephen B. , Herman James G.
Published: October 2019

The promoter region of the cyclin-dependent kinase inhibitorp15INK4Bcontains a CpG island that is hypermethylated in many hematologic malignancies. To explore the relationship between patterns of methylation and gene transcription, we used bisulfite genomic sequencing to obtain a detailed analysis of methylation in acute leukemia, leukemia cell lines, and normal lymphocytes. The entire CpG island region of p15 was largely devoid of methylation in normal lymphocytes, but methylation of varying density was found in primary acute leukemia. Methylation density was generally conserved between the alleles from each sample, but marked heterogeneity for the specific CpG sites methylated was observed. Patterns of methylation were compared and expression assessed with reverse-transcriptase polymerase chain reaction (RT-PCR). The density of methylation within the CpG island, and not any specific location, correlates best with transcriptional loss. Leukemias with methylation of approximately 40% of the CpG dinucleotides on each allele had complete gene silencing, with variable, but diminished expression with less dense CpG island methylation. Our results suggest that the transcriptional silencing of p15 in conjunction with aberrant hypermethylation is best understood as an evolutionary process that involves progressively increasing methylation of the entire p15CpG island.
Functional Analysis of NADPH Oxidase in Granulocytic Cells Expressing a ▵488-497 gp91phox Deletion Mutant
Authors: Yu Lixin , Cross Andrew R. , Zhen Ling , Dinauer Mary C.
Published: October 2019

Chronic granulomatous disease (CGD) is a group of inherited disorders in which phagocytes are unable to generate superoxide (O2−) due to genetic defects in any 1 of 4 essential NADPH oxidase components. Mutations in the X-linked gene for gp91phox, the large subunit of the flavocytochromeb558 heterodimer, account for the majority of CGD. An X-CGD patient in which a splice junction mutation results in an in-frame deletion of 30 nucleotides encoding amino acids 488 to 497 of gp91phox (▵488-497 gp91phox) has previously been reported. In this study, we generated myeloid PLB-985 cells expressing the mutant ▵488-497 gp91phox to further characterize its functional properties. These cells mimicked the phenotype of the patient’s neutrophils with normal expression of a nonfunctional ▵488-497 gp91phox flavocytochrome. Translocation of p47phox and p67phox to ▵488-497 gp91phox PLB-985 plasma membranes was not affected, as determined both in activated intact cells and in the cell-free system. Furthermore, a synthetic peptide corresponding to residues 488-497 of gp91phox was relatively ineffective in inhibiting O2− production in the cell-free oxidase assay (IC50, ∼500 μmol/L), suggesting that residues 488-497 of gp91phox are not directly involved in oxidase assembly. Mutant ▵488-497 gp91phox flavocytochrome failed to support iodonitrotetrazolium (INT) reduction, showing a disruption of electron transfer from NADPH to the FAD center of gp91phox. However, the FAD binding capacity of the mutant flavocytochrome was normal, as measured by equilibrium dialysis. Taken together, these results suggest that the ▵488-497 deletion in gp91phox disrupts electron transfer to FAD, either due to a defect in NADPH binding or to impaired delivery of electrons from NADPH.
Stable Mixed Hematopoietic Chimerism in Dogs Given Donor Antigen, CTLA4Ig, and 100 cGy Total Body Irradiation Before and Pharmacologic Immunosuppression After Marrow Transplant
Authors: Storb Rainer , Yu Cong , Zaucha J. Maciej , Deeg H. Joachim , Georges George , Kiem Hans-Peter , Nash Richard A. , McSweeney Peter A. , Wagner John L.
Published: October 2019

Stable mixed chimerism can be established in dogs given a sublethal dose of 200 cGy total body irradiation (TBI) before and immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP) for 28 and 35 days, respectively, after dog leukocyte antigen-identical marrow transplantation. Most likely, the role of pretransplant TBI was to provide host immunosuppression, since stable mixed chimerism was also achieved in MMF/CSP-treated dogs when 450 cGy irradiation, targeted to cervical, thoracic, and upper abdominal lymph nodes, was substituted for TBI. When TBI was reduced from 200 to 100 cGy, all grafts were rejected within 3 to 12 weeks. Here, we asked whether stable engraftment after 100 cGy TBI could be accomplished by first reducing the intensity of host immune responsiveness with help of the fusion peptide CTLA4Ig, which blocks T-cell costimulation through the B7-CD28 signal pathway. Accordingly, recipient T cells were activated with intravenous (IV) injections of 106 donor peripheral blood mononuclear cells (PBMC)/kg per day on days −7 to −1 before 100 cGy TBI, with concurrent administration of CTLA4Ig 4 mg/kg/d IV. All 7 dogs so treated showed initial mixed chimerism. Two rejected their allografts after 8 and 20 weeks, respectively, and survived with autologous marrow recovery; 1 mixed chimera was unevaluable because of death at 3 weeks from intussusception; and 4 showed persisting mixed chimerism, including unirradiated marrow and lymph node spaces, for now more than 46 to 70 weeks after transplant. Data support the hypothesis that stable marrow allografts can be established by combining nonmyeloablative pretransplant host immunosuppression with posttransplant host and donor cell immunosuppression using MMF/CSP.
Secondary neoplasms subsequent to Berlin-Frankfurt-Münster therapy of acute lymphoblastic leukemia in childhood: significantly lower risk without cranial radiotherapy
Authors: Löning Lutz , Zimmermann Martin , Reiter Alfred , Kaatsch Peter , Henze Günter , Riehm Hansjörg , Schrappe Martin
Published: October 2019

Secondary neoplasms (SNs) represent serious late complications after successful treatment of malignant diseases. To evaluate the rate and type of SNs after Berlin-Frankfurt-Münster (BFM) treatment in children with acute lymphoblastic leukemia (ALL), we analyzed the data from the BFM database and the German Childhood Cancer Registry (GCCR). Between April 1979 and April 1995, 5006 children with B-precursor or T-ALL were enrolled in 5 ALL-BFM multicenter trials. The median follow-up time from diagnosis was 5.7 years (range 1.5-18 years). By December 1997, 52 SNs were documented, including 16 acute myeloid leukemias (AMLs), 13 neoplasms of the central nervous system (CNS), and 23 other neoplasms. Compared with the expected numbers estimated from incidence rates derived from the GCCR, this represented a 14-fold increase for all cancers and a 19-fold increase for CNS tumors. SNs developed 0.9 to 15 years (median: 6 years) after the diagnosis of ALL; 46 patients were in first complete remission (CR). The overall cumulative risk of SNs at 15 years was 3.3% (95% confidence interval [CI]: 1.6%-5.1%) and 2.9% (95% CI: 1.6%-4.2%) in first CR. The risk was 3.5% (95% CI: 1.5%-5.5%) after treatment, including cranial irradiation and significantly lower in nonirradiated patients: 1.2% (95% CI: 0.2%-2.3%;P = .048). The development of secondary AML was not associated with the use of any specific cytotoxic agent. Considering the high-survival rate of this large unselected ALL cohort, the risk of SN is relatively low, though higher, especially after cranial irradiation, than in the general population. Long-term follow-up is mandatory, and further SNs with longer latency periods are to be expected.
Improvement of erythropoiesis in β-thalassemic mice by continuous erythropoietin delivery from muscle
Authors: Bohl Delphine , Bosch Assumpció , Cardona Ana , Salvetti Anna , Heard Jean Michel
Published: October 2019

β-Thalassemias are highly prevalent genetic disorders that can cause severe hemolytic anemia. The main pathophysiologic feature of β-thalassemia is the accumulation of unpaired -globin chains in erythrocyte precursors and red blood cells (RBCs). This accumulation alters cell membrane function and results in early cell destruction and ineffective erythropoiesis. Correction of globin chain imbalance through the induction of fetal hemoglobin (HbF) synthesis is a tentative therapeutic approach for this class of diseases. In short-term in vitro or in vivo assays, recombinant human erythropoietin increases the frequency of erythroid precursors programmed to HbF in humans and to β-minor globin in mice. In contrast, long-term treatment of β-thalassemic patients did not induce HbF significantly. We took advantage of highly efficient adeno-associated virus–mediated (AAV-mediated) gene transfer into mouse muscle to induce a robust and sustained secretion of mouse erythropoietin in β-thalassemic mice, which represent a suitable model for human β-thalassemia intermedia. A 1-year follow-up of 12 treated animals showed a stable correction of anemia associated with improved RBC morphology, increased β-minor globin synthesis, and decreased amounts of -globin chains bound to erythrocyte membranes. More effective erythropoiesis probably accounted for a reduction of erythroid cell proliferation, as shown by decreased proportions of circulating reticulocytes and by reduced iron 59 (59Fe) incorporation into erythroid tissues. This study indicates that the continuous delivery of high amounts of autologous erythropoietin induced a sustained stimulation of β-minor globin synthesis and a stable improvement of erythropoiesis in the β-thalassemic mouse model.
Monocytes express high amounts of Notch and undergo cytokine specific apoptosis following interaction with the Notch ligand, Delta-1
Authors: Ohishi Kohshi , Varnum-Finney Barbara , Flowers David , Anasetti Claudio , Myerson David , Bernstein Irwin D.
Published: October 2019

Notch signaling has been shown to play a key role in cell fate decisions in numerous developmental systems. Using a reverse transcriptase-polymerase chain reaction (RT-PCR) assay, we reported the expression of human Notch-1 in CD34+ progenitors. In this study, we evaluated the expression of human Notch-1 and Notch-2 protein by hematopoietic cells. In immunofluoresence study, we detected low amounts of Notch-1 and Notch-2 protein in both CD34+ and CD34+Lin− cells, high amounts in CD14+ monocytes as well as B and T cells, but no expression in CD15+ granulocytes. We further found that an immobilized truncated form of the Notch ligand, Delta-1, induced apoptosis in monocytes in the presence of macrophage colony-stimulating factor (M-CSF), but not granulocyte-macrophage colony-stimulating factor (GM-CSF). The widespread expressions of Notch proteins suggest multiple functions for this receptor during hematopoiesis. These studies further indicate a novel role for Notch in regulating monocyte survival.
Defensins are dominant HLA-DR-associated self-peptides from CD34− peripheral blood mononuclear cells of different tumor patients (plasmacytoma, chronic myeloid leukemia)
Authors: Halder Thomas M. , Blüggel Martin , Heinzel Susanne , Pawelec Graham , Meyer Helmut E. , Kalbacher Hubert
Published: October 2019

The HLA-DR-associated peptides from peripheral blood mononuclear cells of 2 patients with plasmacytoma and 1 with chronic myeloid leukemia were isolated, identified, and compared. Several were identified as derivatives of the defensin family. Defensins (or human neutrophil peptides [HNP]) are antimicrobial, cationic peptides of 29 to 35 amino acids in length and are the major constituents of the azurophilic granules of human neutrophils. Using peripheral blood cells from leukapheresis, containing about 90% of polymorphonuclear cells, we could identify HNP-1, -2, and -4 and propeptides of up to 49 amino acids in length, eluted from HLA class II molecules. Binding of isolated and synthetic defensin peptides to various HLA-DR alleles using an in vitro binding/competition assay based on size exclusion chromatography revealed that defensin may bind into the peptide-binding groove. In a T-cell competition assay, defensins were able to reduce the proliferation of an HLA-DR-restricted T-cell line after preincubation of stimulating cells (CHO-DRB1*0401 transfectants) with defensin. Therefore, binding of defensins might prevent T-cell recognition of HLA class II molecules expressed on different blood precursor cells (all of which are “nonprofessional” antigen-presenting cells) by blocking the HLA peptide-binding groove or, alternatively, might protect defensin-expressing cells from self-destruction.
P-glycoprotein plays a drug-efflux–independent role in augmenting cell survival in acute myeloblastic leukemia and is associated with modulation of a sphingomyelin-ceramide apoptotic pathway
Authors: Pallis Monica , Russell Nigel
Published: October 2019

P-glycoprotein (pgp), which is the product of the MDR1(multidrug resistance-1) gene, has an established role as a mediator of cytotoxic drug resistance in acute myeloid leukemia (AML). To study the role of pgp in mediating apoptosis resistance in AML cells deprived of serum and growth factors, apoptosis was quantified by flow cytometry using uptake of the dye 7-amino-actinomycin D (7-AAD) alongside low forward scatter. In pgp+ve primary AML samples, there was a significant increase in apoptosis in the presence of the pgp-specific antibody UIC2 (mean increase: 58%; range: 11%-95%; P < .05). Likewise, apoptosis in growth factor–deprived TF1 cells cultured for 30 hours increased 2.5-fold in the presence of 25 μg/mL UIC2. The pgp reversal agent PSC-833 (1 μmol/L) augmented in vitro apoptosis by a median of 52% in pgp+ve patient samples and to a comparable degree in 6 pgp−ve samples. To determine whether the sphingomyelin-ceramide (SM-ceramide) pathway of apoptosis occurs in AML blasts in response to cytotoxic drugs, cells were incubated with daunorubicin at the patient-specific IC30 (the concentration of daunorubicin that caused apoptotic cell death in 30% of cells) in the presence of the ceramide synthase inhibitor fumonisin B1, which inhibited apoptosis by 18%-81% (median: 40%). Exogenous SM failed to augment apoptosis induced by growth factor withdrawal in pgp+ve TF1 cells and was significantly more effective at augmenting apoptosis in pgp−ve patient blasts (median increase in cell death: 33%; range: 19%-88%) than in pgp+ve samples (median: 7%; range: 0%-27%;P = .028). Cellular accumulation of exogenous SM was associated with apoptosis and also occurred in nonapoptotic patient cells treated with PSC-833. However, this effect was not seen following treatment with the UIC2 antibody. These results indicate that pgp is able to exert a protective effect on AML cell viability and that this is associated with a reduced effect of exogenous SM on apoptosis. The pgp reversal agent PSC-833 acts, at least in part, by a pgp independent mechanism to alter SM distribution and to augment apoptosis induced in AML cells by serum and growth factor withdrawal.
Autocrine nerve growth factor is essential for cell survival and viral maturation in HHV-8–infected primary effusion lymphoma cells
Authors: Pica Francesca , Volpi Antonio , Serafino Annalucia , Fraschetti Marzia , Franzese Ornella , Garaci Enrico
Published: October 2019

High levels of nerve growth factor (NGF) are found in sera from individuals infected with human herpesvirus 8 (HHV-8). BC-1 and BCBL-1 cells are primary effusion lymphoma–derived B-cell lines; BC-1 cells are infected by HHV-8 and the Epstein-Barr virus (EBV), and BCBL-1 cells are infected only by HHV-8. Both cells express NGF receptors and produce NGF, whereas RAMOS cells (a B-cell line that is negative for HHV-8 and EBV) express NGF receptors but do not produce detectable NGF. Neutralization of endogenous NGF results in cell growth inhibition and apoptosis in BCBL-1 cells and, to a minor extent, in BC-1 cells. When the HHV-8 lytic cycle is induced in BCBL-1 cells by tetradecanoyl phorbol acetate (TPA), an initial reduction of endogenous NGF production is observed, and many cells undergo apoptosis. However, at 48 hours, TPA-treated cells produce significantly more NGF than untreated controls, and a subsequent recovery of cell viability is observed. Consistent with this finding, the addition of exogenous NGF or anti-NGF antibodies to TPA-treated cells reduces or increases, respectively, the rate of apoptosis in response to TPA. Finally, electron microscopy of TPA-treated BCBL-1 cells shows that the addition of exogenous NGF increases the number of cells producing and releasing complete virions as compared with the controls (25% versus 5%). On the contrary, NGF neutralization leads to the production of defective viral progeny in about 2% of cells. These data indicate that NGF is essential for both cell survival and virus maturation in HHV-8–infected cell lines.
Analysis of the biologic properties of p230 Bcr-Abl reveals unique and overlapping properties with the oncogenic p185 and p210 Bcr-Abl tyrosine kinases
Authors: Quackenbush Robert C. , Reuther Gary W. , Miller Juli P. , Courtney Kevin D. , Pear Warren S. , Pendergast Ann Marie
Published: October 2019

The reciprocal translocation between chromosomes 9 and 22 that fuses coding sequences of the Bcr and Abl genes is responsible for a remarkably diverse group of hematologic malignancies. A newly described 230-kd form of Bcr-Abl has been associated with an indolent myeloproliferative syndrome referred to as chronic neutrophilic leukemia. We have cloned the corresponding gene and examined the biologic and biochemical properties of p230 Bcr-Abl after retroviral-mediated gene transfer into hematopoietic cell lines and primary bone marrow cells. p230 Bcr-Abl–expressing 32D myeloid cells were fully growth factor-independent and activated similar signal transduction pathways as the well-characterized p210 and p185 forms of Bcr-Abl. In contrast, primary mouse bone marrow cells expressing p230 required exogenous hematopoietic growth factors for optimal growth, whereas p185- and p210-expressing cells were independent of growth factors. The 3 Bcr-Abl proteins exerted different effects on differentiation of bone marrow cells. p185 induced outgrowth of lymphoid precursors capable of tumor formation in immunodeficient mice. In contrast, p210- and p230-expressing bone marrow cells caused limited outgrowth of lymphoid precursors that failed to form tumors in immunodeficient mice. Removal of cytokines and autologous stroma from Bcr-Abl–expressing bone marrow cultures produced the expansion of distinct lineages by the various Bcr-Abl proteins. p185 drove expansion of cytokine-independent lymphoid progenitors, while p210 and p230 generated cytokine-independent monocyte/myeloid cells. These findings suggest that the different Bcr-Abl fusion proteins drive the expansion of different hematopoietic populations, which may explain the association of the various Bcr-Abl oncoproteins with different spectra of human leukemias.
Loss of heterozygosity on 10q and microsatellite instability in advanced stages of primary cutaneous T-cell lymphoma and possible association with homozygous deletion of PTEN
Authors: Scarisbrick Julia J. , Woolford Alison J. , Russell-Jones Robin , Whittaker Sean J.
Published: October 2019

Previous cytogenetic studies of primary cutaneous T-cell lymphoma (CTCL) were based on limited numbers of patients and seldom showed consistent nonrandom chromosomal abnormalities. In this study, 54 tumor DNA samples from patients with CTCL were analyzed for loss of heterozygosity on 10q. Allelic loss was identified in 10 samples, all of which were from the 44 patients with mycosis fungoides (10/44 patients; 23%). Of the patients with allelic loss, 3 were among the 29 patients with early-stage myosis fungoides (T1 or T2) (3/29 patients; 10%), whereas the other 7 were among the 15 patients with advanced cutaneous disease (T3 or T4) (7/15 patients; 47%). The overlapping region of deletion was between 10q23 and 10q24. In addition, microsatellite instability (MSI) was present in 13 of the 54 samples (24%), 12 from patients with mycosis fungoides and 1 from a patient with Sezary syndrome. There was also an association between MSI and disease progression in patients with mycosis fungoides, with 6 of 15 (40%) patients with MSI having advanced cutaneous disease and only 6 of 29 (21%) having early-stage disease. Samples with allelic loss on 10q were analyzed for abnormalities of the tumor suppressor genePTEN (10q23.3). No tumor-specific mutations were detected, but homozygous deletion was found in 2 patients. Thus, we found loss of heterozygosity on 10q and MSI in advanced cutaneous stages of mycosis fungoides. These findings indicate that a tumor suppressor gene or genes in this region may be associated with disease progression. Furthermore, abnormalities of PTEN may be important in the pathogenesis of mycosis fungoides, but our data imply that this gene is rarely inactivated by small deletions or point mutations.
Selectively increased growth of fetal hemoglobin-expressing adult erythroid progenitors after brief treatment of early progenitors with transforming growth factor beta
Authors: Bohmer Ralph M. , Campbell Thomas A. , Bianchi Diana W.
Published: October 2019

We have studied the effect of transforming growth factor beta (TGFβ) on erythropoiesis in cultures from adult peripheral blood, using flow cytometric enumeration of fetal hemoglobin (HbF)-containing cells. TGFβ caused a dramatic increase in the proportions of cells that accumulated HbF together with adult hemoglobin (HbA) (F+A+ cells). This highly significant (P < .0001) increase in F+ cell proportion was achieved by TGFβ treatment during the first 4 days of culture and was sustained during further culture expansion in the absence of TGFβ. The increase in F+ cell proportions did not depend on the cytokine combination (EPO+SCF+IL3, EPO+SCF, EPO+IL3, SCF+IL3) used during the phase of TGFβ treatment. Increased F+ cell proportions were paralleled by an increased molecular ratio of HbF/ HbF+ HbA, measured by cation exchange high-performance liquid chromatography (HPLC). In addition to the effect on F+ cell proportions, TGFβ caused a dramatic increase in overall cell division potential. By the time cultures reached terminal growth arrest (12-14 days in controls and 18-26 days after TGFβ), the overall numbers of F+ cells produced per initially seeded clonogenic cell was approximately 10 times higher in the TGFβ-treated cultures than in the controls. We propose to investigate whether the TGFβ-induced increase in relative and absolute numbers of nucleated F+ cells, as demonstrated in vitro, can be translated into increased F+ erythrocytes in vivo, allowing therapeutic application for some beta-hemoglobinopathies.
Down-regulation of L-selectin expression in neutrophils by nonsteroidal anti-inflammatory drugs: role of intracellular ATP concentration
Authors: Gómez-Gaviro Maria Victoria , Domı́nguez-Jiménez Carmen , Carretero Jorge Moreno , Sabando Pedro , González-Alvaro Isidoro , Sánchez-Madrid Francisco , Dı́az-González Federico
Published: October 2019

L-selectin is an adhesion molecule that plays an essential role in the early events of the inflammatory response. Our group has recently described that several nonsteroidal anti-inflammatory drugs (NSAIDs) are able to induce both in vivo and in vitro the shedding of L-selectin in neutrophils through an unknown mechanism. In this work, we have studied potential mechanisms involved in the shedding of L-selectin induced by NSAIDs. This effect of NSAIDs did not involve any detectable intracellular calcium flux. Pretreatment of neutrophils either with Ro 31-8220 and H7, 2 specific inhibitors of protein kinase C (PKC), or with inhibitors of protein tyrosine kinases such as tyrphostin A25 or herbimycin A did not prevent the NSAID-mediated L-selectin shedding. However, the KD-IX-73-4, an inhibitor of L-selectin proteolysis was able to block the effect of NSAIDs on L-selectin expression. Remarkably, NSAIDs caused a variable reduction in the neutrophil intracellular ATP concentration that highly correlated with the differential ability of NSAIDs to trigger L-selectin shedding (r = 0.8, P < .01). In agreement with this finding, azide plus 2-deoxy-D-glucose, 2 metabolic blockers, also induced a rapid L-selectin shedding (65% ± 8%) without affecting the neutrophil viability, activation, or expression level of other surface molecules with soluble isoforms such as CD16 and CD59. These data indicate that the maintenance of L-selectin on the neutrophil surface requires energy consumption, which suggests that L-selectin is shed in neutrophils by default. Interestingly, NSAIDs seem to cause the shedding of L-selectin, at least in part, through the reduction of the intracellular ATP concentration.
Receptor binding cancer antigen expressed on SiSo cells, a novel regulator of apoptosis of erythroid progenitor cells
Authors: Matsushima Takamitsu , Nakashima Manabu , Oshima Koichi , Abe Yasunobu , Nishimura Junji , Nawata Hajime , Watanabe Takeshi , Muta Koichiro
Published: October 2019

To better understand the control of apoptosis during erythropoiesis, this study investigated the role of a novel tumor-associated antigen, RCAS1 (receptor binding cancer antigen expressed on SiSo cells), with regard to the regulation of apoptosis of erythroid progenitor cells. Erythroid colony-forming cells (ECFCs) purified from human peripheral blood were used. Binding experiments of RCAS1 showed that ECFCs abundantly expressed receptors (RCAS1R) for RCAS1 and that the degree of binding of RCAS1 to the receptors diminished rapidly during erythroid maturation in vitro. When the soluble form of RCAS1 was added to the cultures, ECFCs underwent apoptosis, including collapse of the mitochondrial transmembrane potential, and activation of caspases 8 and 3. The addition of an anti-Fas blocking antibody or Fas-Fc failed to reduce the apoptosis induced by RCAS1, thereby indicating that effects of RCAS1 are independent of Fas activation. When binding of RCAS1 to normal bone marrow cells was analyzed, RCAS1R was evident on cells with an immature erythroid phenotype (transferrin receptor+/glycophorin A−) but not with a mature phenotype (transferrin receptor−/glycophorin A+). Histochemical staining revealed the expression of RCAS1 in the cytoplasm of bone marrow macrophages. These findings indicate that RCAS1, which is mainly produced by macrophages in hematopoietic tissue, may have a crucial role in controlling erythropoiesis by modulating apoptosis of erythroid progenitor cells via a Fas-independent mechanism.
Defects in leukocyte-mediated initiation of lipid peroxidation in plasma as studied in myeloperoxidase-deficient subjects: systematic identification of multiple endogenous diffusible substrates for myeloperoxidase in plasma
Authors: Zhang Renliang , Shen Zhongzhou , Nauseef William M. , Hazen Stanley L.
Published: October 2019

More than a decade ago it was demonstrated that neutrophil activation in plasma results in the time-dependent formation of lipid hydroperoxides through an unknown, ascorbate-sensitive pathway. It is now shown that the mechanism involves myeloperoxidase (MPO)-dependent use of multiple low-molecular–weight substrates in plasma, generating diffusible oxidant species. Addition of activated human neutrophils (from healthy subjects) to plasma (50%, vol/vol) resulted in the peroxidation of endogenous plasma lipids by catalase-, heme poison-, and ascorbate-sensitive pathways, as assessed by high-performance liquid chromatography (HPLC) with on-line electrospray ionization tandem mass spectrometric analysis of free and lipid-bound 9-HETE and 9-HODE. In marked contrast, neutrophils isolated from multiple subjects with MPO deficiency failed to initiate peroxidation of plasma lipids, but they did so after supplementation with isolated human MPO. MPO-dependent use of a low-molecular–weight substrate(s) in plasma for initiating lipid peroxidation was illustrated by demonstrating that the filtrate of plasma (10-kd MWt cutoff) could supply components required for low-density lipoprotein lipid peroxidation in the presence of MPO and H2O2. Subsequent HPLC fractionation of plasma filtrate (10-kd MWt cutoff) by sequential column chromatography identified nitrite, tyrosine, and thiocyanate as major endogenous substrates and 17β-estradiol as a novel minor endogenous substrate in plasma for MPO in promoting peroxidation of plasma lipids. These results strongly suggest that the MPO–H2O2system of human leukocytes serves as a physiological mechanism for initiating lipid peroxidation in vivo.
An application of machine learning with feature selection to improve diagnosis and classification of neurodegenerative disorders
Authors: Álvarez Josefa Díaz , Matias-Guiu Jordi A. , Cabrera-Martín María Nieves , Risco-Martín José L. , Ayala José L.
Published: October 2019

Background

The analysis of health and medical data is crucial for improving the diagnosis precision, treatments and prevention. In this field, machine learning techniques play a key role. However, the amount of health data acquired from digital machines has high dimensionality and not all data acquired from digital machines are relevant for a particular disease. Primary Progressive Aphasia (PPA) is a neurodegenerative syndrome including several specific diseases, and it is a good model to implement machine learning analyses. In this work, we applied five feature selection algorithms to identify the set of relevant features from 18F-fluorodeoxyglucose positron emission tomography images of the main areas affected by PPA from patient records. On the other hand, we carried out classification and clustering algorithms before and after the feature selection process to contrast both results with those obtained in a previous work. We aimed to find the best classifier and the more relevant features from the WEKA tool to propose further a framework for automatic help on diagnosis. Dataset contains data from 150 FDG-PET imaging studies of 91 patients with a clinic prognosis of PPA, which were examined twice, and 28 controls. Our method comprises six different stages: (i) feature extraction, (ii) expertise knowledge supervision (iii) classification process, (iv) comparing classification results for feature selection, (v) clustering process after feature selection, and (vi) comparing clustering results with those obtained in a previous work.

Results

Experimental tests confirmed clustering results from a previous work. Although classification results for some algorithms are not decisive for reducing features precisely, Principal Components Analisys (PCA) results exhibited similar or even better performances when compared to those obtained with all features.

Conclusions

Although reducing the dimensionality does not means a general improvement, the set of features is almost halved and results are better or quite similar. Finally, it is interesting how these results expose a finer grain classification of patients according to the neuroanatomy of their disease.
DECA: scalable XHMM exome copy-number variant calling with ADAM and Apache Spark
Authors: Linderman Michael D. , Chia Davin , Wallace Forrest , Nothaft Frank A.
Published: October 2019

Background

XHMM is a widely used tool for copy-number variant (CNV) discovery from whole exome sequencing data but can require hours to days to run for large cohorts. A more scalable implementation would reduce the need for specialized computational resources and enable increased exploration of the configuration parameter space to obtain the best possible results.

Results

DECA is a horizontally scalable implementation of the XHMM algorithm using the ADAM framework and Apache Spark that incorporates novel algorithmic optimizations to eliminate unneeded computation. DECA parallelizes XHMM on both multi-core shared memory computers and large shared-nothing Spark clusters. We performed CNV discovery from the read-depth matrix in 2535 exomes in 9.3 min on a 16-core workstation (35.3× speedup vs. XHMM), 12.7 min using 10 executor cores on a Spark cluster (18.8× speedup vs. XHMM), and 9.8 min using 32 executor cores on Amazon AWS’ Elastic MapReduce. We performed CNV discovery from the original BAM files in 292 min using 640 executor cores on a Spark cluster.

Conclusions

We describe DECA’s performance, our algorithmic and implementation enhancements to XHMM to obtain that performance, and our lessons learned porting a complex genome analysis application to ADAM and Spark. ADAM and Apache Spark are a performant and productive platform for implementing large-scale genome analyses, but efficiently utilizing large clusters can require algorithmic optimizations and careful attention to Spark’s configuration parameters.
The impact of dexmedetomidine added to ropivicaine for transversus abdominis plane block on stress response in laparoscopic surgery: a randomized controlled trial
Authors: Qin Zhaojun , Xiang Chunyan , Li Hongbo , Liu Tingting , Zhan Leyun , Xia Zhengyuan , Zhang Min , Lai Jianping
Published: October 2019

Background

Intravenous dexmedetomidine is known to attenuate stress response in patients undergoing laparoscopic surgery. We investigated whether the addition of the highly selective alpha-2 adrenergic agonist dexmedetomidine into ropivacaine for ultrasound-guided transversus abdominis plane block could inhibit stress response during laparoscopic surgery, and determined the optimal dose of dexmedetomidine in it.

Methods

One hundred and twenty-five patients undergoing laparoscopic gynecological surgery were included in this prospective and randomized double-blind study. Patients received general anesthesia with or without a total of 60 ml of 0.2% ropivacaine in combination with low (0.25 μg/kg), medium (0.50 μg/kg) or high dose (1.0 μg/kg) of dexmedetomidine for the four-quadrant transversus abdominis plane block (n = 25). The primary outcomes were stress marker levels during the operation.

Results

One hundred and twenty patients completed the study protocol. Dexmedetomidine added to ropivacaine for transversus abdominis plane block significantly reduced serum levels of cortisol, norepinephrine, epinephrine, interleukin-6, blood glucose, mean arterial pressure and heart rate in a dose-dependent manner (P < 0.05), accompanied with decreased anesthetic and opioid consumption during the operation (P < 0.05), but the high dose of dexmedetomidine induced higher incidences of bradycardia than low or medium dose of dexmedetomidine (P < 0.05).

Conclusion

The addition of dexmedetomidine at the dose of 0.5 μg/kg into ropivacaine for ultrasound-guided transversus abdominis plane block is the optimal dose to inhibit stress response with limited impact on blood pressure and heart rate in patients undergoing laparoscopy gynecological surgery.

Trial registration

This study was registered atwww.chictr.org.cnon November 6th, 2016 (ChiCTR-IOR-16009753).
Infantile hepatic hemangiomas associated with high-output cardiac failure and pulmonary hypertension
Authors: Zhang Xin-tong , Ren Wei-dong , Song Guang , Xiao Yang-jie , Sun Fei-fei , Wang Nan
Published: October 2019

Background

Infantile hepatic hemangioma (IHH) is a rare endothelial cell neoplasm, which may be concurrent with severe complications and result in poor outcomes. Moreover, the coexistence of IHH and congenial heart disease is even rarer.

Case presentation

We present a 10-day-old male born with IHH associated with patent ductus arteriosus (PDA), atrial septal defect (ASD) and pulmonary hypertension. Moreover, we reviewed a series of studies of IHH-associated high-output cardiac failure between 1974 and 2018, and summarized the treatment outcomes.

Conclusions

Infantile hepatic hemangioma (IHH) has been known to induce high-output heart failure. There is no literature to summarize the severity of its impact on heart, which can lead to a high mortality rate. When IHH is detected by ultrasound, the heart should be evaluated to facilitate treatment. The outcomes of IHH associated with heart failure are good.
Knowledge of tuberculosis among female sex workers in Rajshahi city, Bangladesh: a cross sectional study
Authors: Rana Md. Masud , Islam Md. Rafiqul , MoinUddin Sheikh , Wadood Md. Abdul , Hossain Md. Golam
Published: October 2019

Background

Tuberculosis (TB) is a major public health problem in developing countries like Bangladesh. Female sex workers (FSWs) and their clients are active sources for spreading TB. The purpose of this study was to assess the knowledge of TB among FSWs in Rajshahi city, Bangladesh.

Methods

It was a cross-sectional study with a sample size of 225 FSWs. The knowledge on TB was measured by six different questions. Chi-square test and multinomial logistic regression model were used in this study to find the associated factors of lack of general knowledge on TB among FSWs.

Results

Out of 225 FSWs, 43.1, 34.7 and 22.2% came from urban, rural and slum areas respectively. More than 41% FSWs perceived that TB is a non-communicable disease. A large number of FSWs (76.4%) did not know the spread of TB. It was found that more than 90% FSWs did not have knowledge on latent TB. The χ2-test demonstrated that FSWs’ education, monthly family income, age, currently marital status and sex trading place were significantly associated with their knowledge on TB. A remarkable number of FWSs (42.2%) had poor knowledge on TB. It was found that comparatively higher educated FWSs were more likely to have good or fair knowledge on TB than lower educated ones (p < 0.01).

Conclusions

This study revealed that near to half of FSWs in Rajshahi city, Bangladesh had poor knowledge on TB. Public health authorities should pay due attention and adopt policy for increasing the knowledge on TB among FSWs to reduce the incidence of TB in Bangladesh. Subsequently, advocacy, communication for social mobilization program is very urgent.
Depression and anxiety among people living with and beyond cancer: a growing clinical and research priority
Authors: Niedzwiedz Claire L. , Knifton Lee , Robb Kathryn A. , Katikireddi Srinivasa Vittal , Smith Daniel J.
Published: October 2019

Background

A cancer diagnosis can have a substantial impact on mental health and wellbeing. Depression and anxiety may hinder cancer treatment and recovery, as well as quality of life and survival. We argue that more research is needed to prevent and treat co-morbid depression and anxiety among people with cancer and that it requires greater clinical priority. For background and to support our argument, we synthesise existing systematic reviews relating to cancer and common mental disorders, focusing on depression and anxiety.

We searched several electronic databases for relevant reviews on cancer, depression and anxiety from 2012 to 2019. Several areas are covered: factors that may contribute to the development of common mental disorders among people with cancer; the prevalence of depression and anxiety; and potential care and treatment options. We also make several recommendations for future research. Numerous individual, psychological, social and contextual factors potentially contribute to the development of depression and anxiety among people with cancer, as well as characteristics related to the cancer and treatment received. Compared to the general population, the prevalence of depression and anxiety is often found to be higher among people with cancer, but estimates vary due to several factors, such as the treatment setting, type of cancer and time since diagnosis. Overall, there are a lack of high-quality studies into the mental health of people with cancer following treatment and among long-term survivors, particularly for the less prevalent cancer types and younger people. Studies that focus on prevention are minimal and research covering low- and middle-income populations is limited.

Conclusion

Research is urgently needed into the possible impacts of long-term and late effects of cancer treatment on mental health and how these may be prevented, as increasing numbers of people live with and beyond cancer.
A theory of public wellbeing
Authors: Fisher Matthew
Published: October 2019

Background

Wellbeing is seen as a matter of concern for governments and public policy. However, current theories on wellbeing are not well placed to inform this concern, because they fail to take account of and explain evidence on social determinants of mental health.

Discussion

This article proposes a new theory of public wellbeing which does takes account of such evidence, by explaining the role of stress within three basic functions of social cognition. Building on this description, the article then proposes that wellbeing consists in seven basic abilities, which are always developed and exercised (or not) through constant processes of interaction between individual and environment. The article explains why contemporary theories on wellbeing are poorly placed to inform public policy for wellbeing. It also positions the proposed theory in relation to evidence on social determinants of health (SDH) and the associated public policy agenda. It is argued the proposed theory of wellbeing extends on and challenges the SDH policy agenda in relation to the normative target of policy proposals, factors identified as determinants, impacts of determinants on populations, and proposals for political and social change.

Conclusion

Improved theory on public wellbeing can inform policy for wellbeing because it explains the contingent nature of wellbeing within contemporary social environments, and extends understanding of social determinants of wellbeing.