bluuebunny/crossref_metadata_2025 huggingface dataset:
Unmutated Ig VH Genes Are Associated With a More Aggressive Form of Chronic Lymphocytic Leukemia
Authors: Hamblin Terry J. , Davis Zadie , Gardiner Anne , Oscier David G. , Stevenson Freda K.
Published: October 2019

Despite having several characteristics of naı̈ve B cells, chronic lymphocytic leukemia (CLL) cells have been shown in some cases to have somatically mutated Ig variable region genes, indicating that the cell of origin has passed through the germinal center. A previous study of patients with CLL found an association between lack of somatic mutation and trisomy 12 and, therefore, possibly with a less favorable prognosis. We have sequenced the Ig VH genes of the tumor cells of 84 patients with CLL and correlated our findings with clinical features. A total of 38 cases (45.2%) showed ≥ 98% sequence homology with the nearest germline VH gene; 46 cases (54.8%) showed >2% somatic mutation. Unmutated VH genes were significantly associated with V1-69 and D3-3 usage, with atypical morphology; isolated trisomy 12, advanced stage and progressive disease. Survival was significantly worse for patients with unmutated VH genes irrespective of stage. Median survival for stage A patients with unmutated VH genes was 95 months compared with 293 months for patients whose tumors had mutated VHgenes (P = .0008). The simplest explanation is that CLL comprises 2 different diseases with different clinical courses. One, arising from a memory B cell, has a benign course, the other, arising from a naı̈ve B cell, is more malignant.
The (4;11)(q21;p15) Translocation Fuses the NUP98 andRAP1GDS1 Genes and Is Recurrent in T-Cell Acute Lymphocytic Leukemia
Authors: Hussey Damian J. , Nicola Mario , Moore Sarah , Peters Gregory B. , Dobrovic Alexander
Published: October 2019

We determined the breakpoint genes of the translocation t(4;11)(q21;p15) that occurred in a case of adult T-cell acute lymphocytic leukemia (T-ALL). The chromosome 11 breakpoint was mapped to the region between D11S470 and D11S860. The nucleoporin 98 gene (NUP98), which is rearranged in several acute myeloid leukemia translocations, is located within this region. Analysis of somatic cell hybrids segregating the translocation chromosomes showed that the chromosome 11 breakpoint occurs withinNUP98. The fusion partner of NUP98 was identified as theRAP1GDS1 gene using 3′ RACE. RAP1GDS1 codes for smgGDS, a ubiquitously expressed guanine nucleotide exchange factor that stimulates the conversion of the inactive GDP-bound form of several ras family small GTPases to the active GTP-bound form. In theNUP98-RAP1GDS1 fusion transcript (abbreviated asNRG), the 5′ end of the NUP98 gene is joined in frame to the coding region of the RAP1GDS1 gene. This joins the FG repeat-rich region of NUP98 to RAP1GDS1, which largely consists of tandem armadillo repeats. NRG fusion transcripts were detected in the leukemic cells of 2 other adult T-ALL patients. One of these patients had a variant translocation with a more 5′ breakpoint in NUP98. This is the first report of anNUP98 translocation in lymphocytic leukemia and the first time that RAP1GDS1 has been implicated in any human malignancy.
Analysis of Warfarin Therapy in Pediatric Patients: A Prospective Cohort Study of 319 Patients
Authors: Streif W. , Andrew M. , Marzinotto V. , Massicotte P. , Chan A.K.C. , Julian J.A. , Mitchell L.
Published: October 2019

This study details warfarin use in a large pediatric population followed in a central anticoagulation clinic. A prospective, consecutive cohort of nonselected children were studied. Patients were divided into groups by age, target international normalized ratio (INR) range, disease, medications, and vitamin K supplemented enteral nutrition use. Groups were analyzed on multiple aspects of warfarin therapy using multivariate methods. A total of 319 patients received 352 warfarin courses representing 391 treatment years. Age independently influenced all aspects of therapy. When compared with all older children, the ≤1 year of age group required increased warfarin doses, longer overlap with heparin, longer time to achieve target INR ranges, more frequent INR testing and dose adjustments, and fewer INR values in the target range. Although significantly different than children ≤1 year, children 1 to 6 years of age showed the same findings when compared with 7- to 18-year-olds. Fontan patients required 25% decreased dosage as compared with other congenital heart disease patients. Children on corticosteroids had less INRs in the target range and children on phenobarbital/carbamazepine required increased maintenance dosages of warfarin. Also, patients receiving enteral nutrition required increased dosages of warfarin. Serious bleeding occurred in 2 children (0.5% per patient year). Recurrent thromboembolic events (TEs) occurred in 8 children. Two children had recurrences while receiving warfarin (1.3% per patient year). This study outlines the profound effect of age and relative complexity of clinical management of warfarin therapy in children.
Shwachman-Diamond Syndrome: An Inherited Preleukemic Bone Marrow Failure Disorder With Aberrant Hematopoietic Progenitors and Faulty Marrow Microenvironment
Authors: Dror Yigal , Freedman Melvin H.
Published: October 2019

Shwachman-Diamond syndrome (SD), an inherited disorder with varying cytopenias and a marked tendency for malignant myeloid transformation, is an important model for understanding genetic determinants in hematopoiesis. To define the basis for the faulty hematopoietic function, 13 patients with SD (2 of whom had myelodysplasia with a clonal cytogenetic abnormality) and 11 healthy marrow donors were studied. Patients with SD had significantly lower numbers of CD34+ cells on bone marrow aspirates. SD CD34+ cells plated directly in standard clonogenic assays showed markedly impaired colony production potential, underscoring an intrinsically aberrant progenitor population. To assess marrow stromal function, long-term marrow stromal cell cultures (LTCs) were established. Normal marrow CD34+ cells were plated over either SD stroma (N/SD) or normal stroma (N/N); SD CD34+cells were plated over either SD stroma (SD/SD) or normal stroma (SD/N). Nonadherent cells harvested weekly from N/SD LTCs were strikingly reduced compared with N/N LTCs; numbers of granulocyte-monocyte colony-forming units (CFU-GM) derived from N/SD nonadherent cells were also lower. SD/N showed improved production of nonadherent cells and CFU-GM colonies compared with SD/SD, but much less than N/N. Stem-cell and stromal properties from the 2 patients with SD and myelodysplasia did not differ discernibly from SD patients without myelodysplasia. We conclude that in addition to a stem-cell defect, patients with SD have also a serious, generalized marrow dysfunction with an abnormal bone marrow stroma in terms of its ability to support and maintain hematopoiesis. This dual defect exists in SD with and without myelodysplasia.
Seeding Efficiency of Primitive Human Hematopoietic Cells in Nonobese Diabetic/Severe Combined Immune Deficiency Mice: Implications for Stem Cell Frequency Assessment
Authors: van Hennik Paula B. , de Koning Alexandra E. , Ploemacher Rob E.
Published: October 2019

Nonobese diabetic/severe combined immune deficiency (NOD/SCID) mouse repopulating cells (SRC) have been proposed to represent a more primitive human stem cell subset than the cobblestone area-forming cell (CAFC) week (wk) 6 or the long-term culture-initiating cell (LTC-IC) wk 5 on the basis of their difference in frequency, phenotype, transfectibility, and multilineage outgrowth potential in immunodeficient recipients. We have assessed the percentage of various progenitor cell populations (colony-forming cell [CFC] and CAFC subsets) contained in unsorted NOD/SCID BM nucleated cells (nc), human umbilical cord blood (UCB) nc, bone marrow (BM) nc, peripheral blood stem cells (PBSC), and CD34+ selected UCB nc, seeding in the BM and spleen of NOD/SCID mice within 24 hours after transplantation. The seeding efficiency of NOD/SCID BM CAFC wk 5 was median (range) in the spleen 2.9% (0.7% to 4.0%) and in the total BM 8.7% (2.0% to 9.2%). For human unsorted UCB nc, BM nc, PBSC, and CD34+ UCB cells, the seeding efficiency for CAFC wk 6 in the BM of NOD/SCID mice was 4.4% (3.5% to 6.3%), 0.8% (0.3% to 1.7%), 5.3% (1.4% to 13.6%), and 4.4% (3.5% to 6.3%), respectively. Using flow cytometry, the percentage CD34+UCB cells retrieved from the BM of sublethally or supralethally irradiated NOD/SCID mice was 2.3 (1.4 to 2.8) and 2.5 (1.6 to 2.7), respectively. Because we did not observe any significant differences in the seeding efficiencies of the various stem cell subsets, it may be assumed that the SRC seeding efficiency in NOD/SCID mice is similarly low. Our data indicate that the seeding efficiency of a graft can be of great influence when assessing stem cell frequencies in in vivo repopulation assays.
CD137 Induces Proliferation and Endomitosis in Monocytes
Authors: Langstein Joachim , Michel Jan , Schwarz Herbert
Published: October 2019

Peripheral monocytes are short-lived and are replenished from hematopoietic stem cells whose proliferation is believed to be confined to the bone marrow. Human peripheral monocytes are assumed not to be able to proliferate. In this study we show that CD137 (ILA/4-1BB), a member of the tumor necrosis factor receptor family, induces a widespread and profound proliferation of human peripheral monocytes. Macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor are essential, but not sufficient for proliferation. Additional soluble autocrine factors induced by CD137 are required. Induction of proliferation is mediated via reverse signaling through a CD137 ligand, expressed constitutively by peripheral monocytes. The ability of CD137 to induce proliferation in human peripheral monocytes is not shared by any other known molecule.
Simultaneous Ex Vivo Expansion of Cytomegalovirus and Epstein-Barr Virus–Specific Cytotoxic T Lymphocytes Using B-Lymphoblastoid Cell Lines Expressing Cytomegalovirus pp65
Authors: Sun Qi , Pollok Karen E. , Burton Robert L. , Dai Li Jun , Britt William , Emanuel David J. , Lucas Kenneth G.
Published: October 2019

Cytomegalovirus (CMV) infection and Epstein-Barr virus (EBV)-induced lymphoproliferative disease are serious complications associated with allogeneic stem cell transplantation. Immunotherapy using ex vivo expanded, virus-specific cytotoxic T lymphocytes (CTL) has been explored and proven to be effective in therapeutic or prophylactic regimens for CMV and EBV infections. To generate CTL specific for both CMV and EBV, we engineered EBV-transformed B-lymphoblastoid cell lines (BLCL) to express CMV pp65 for use as antigen-presenting cells (APC). BLCL were transduced with a recombinant retrovirus encoding pp65, the immunodominant CMV polypeptide. Western blot analysis and immunocytochemistry confirmed the expression of pp65 in the transduced cells. Peripheral blood mononuclear cells (PBMC) from healthy CMV seropositive donors were stimulated with autologous pp65-expressing BLCL weekly for 3 weeks. Chromium release assays showed that the resulting CTL cultures possessed specific cytotoxicity against EBV and CMV. Recombinant vaccinia viruses encoding individual CMV peptides were used to demonstrate that this CMV-specific cytotoxicity was specific for pp65. Assays on CD4- and CD8-depleted CTL fractions indicated that CD8+ CTL mediated the pp65-specific cytotoxicity. These CMV/EBV-specific CTL recognized CMV- and EBV-infected targets sharing HLA class I antigens, but not HLA mismatched targets. Our results demonstrate that BLCL can be used as APC to stimulate expansion of EBV- and CMV-specific CTL simultaneously. These findings have potential implications for posttransplant CMV and EBV immunotherapy in recipients of allogeneic stem cell transplants.
Expression and coreceptor activity of STRL33/Bonzo on primary peripheral blood lymphocytes
Authors: Sharron Matthew , Pöhlmann Stefan , Price Ken , Lolis Elias , Tsang Monica , Kirchhoff Frank , Doms Robert W. , Lee Benhur
Published: October 2019

CCR5 and CXCR4 are the major coreceptors that mediate human immunodeficiency virus 1 (HIV-1) infection, while most simian immunodeficiency virus (SIV) isolates use CCR5. A number of alternative coreceptors can also mediate infection of some virus strains in vitro, although little is known about their in vivo relevance. Therefore, we characterized the expression pattern and coreceptor activity of one of these alternative coreceptors, STRL33/Bonzo, using a newly developed monoclonal antibody. In addition to being highly expressed (approximately 1000-7000 STRL33 ABS [antibody binding sites]) on specific subsets of natural killer cells (CD3−/CD16−/low/CD56+ and CD3−/CD16low/CD56−) and CD19+ B lymphocytes (approximately 300-5000 STRL33 ABS), STRL33 was expressed at levels sufficient to support virus infection on freshly isolated, truly naive CD4+/CD45RA+/CD62L+cells (6000-11 000 ABS). STRL33 expression on peripheral blood mononuclear cells (PBMCs) was increased by mitogenic stimulation (OKT3/IL-2 [interleukin-2] had a greater effect than phytohemaglutinin (PHA)/IL-2), but it was dramatically decreased upon Ficoll purification. Infection of CCR5− human peripheral blood lymphocytes (PBLs) showed that 2 different SIV envelope (Env) proteins mediated entry into STRL33+cells. More importantly, the preferential infection of STRL33+ cells in CCR5− PBLs by an R5/X4/STRL33 HIV-1 maternal isolate in the presence of a potent CXCR4 antagonist (AMD3100) suggests that STRL33 can be used as a coreceptor by HIV-1 on primary cells. Rhesus macaque (rh) STRL33 was used less efficiently than human STRL33 by the majority of SIV Env proteins tested despite similar levels of expression, thereby making it less likely that STRL33 is a relevant coreceptor in the rhesus macaque system. In summary, the expression pattern and coreceptor activity of STRL33 suggest its involvement in trafficking of tumor-infiltrating lymphocytes and indicate that STRL33 may be a relevant coreceptor in vivo.
An in vivo competitive repopulation assay for various sources of human hematopoietic stem cells
Authors: Rosler Elen S. , Brandt John E. , Chute John , Hoffman Ronald
Published: October 2019

The marrow repopulating potential (MRP) of different sources of human hematopoietic stem cells (HSCs) was directly compared using an in vivo assay in which severe combined immunodeficient disease (SCID) mice were implanted with human fetal bones. HSCs from 2 human lymphocyte antigen (HLA)-mismatched donors were injected individually or simultaneously into the fetal bones of a 3rd distinct HLA type and donor and recipient myeloid and lymphoid cells were identified after 8 to 10 weeks. The study compared the MRP of umbilical cord blood (CB) and adult bone marrow (ABM) CD34+ cells as well as grafts of each type expanded ex vivo. Equal numbers of CB and ABM CD34+ cells injected individually demonstrated similar abilities to establish multilineage hematopoiesis. However, when CB and ABM cells were transplanted simultaneously, the engraftment of CB cells was markedly superior to ABM. CB and ABM CD34+ cells were expanded ex vivo using either a porcine microvascular endothelial cell (PMVEC)-based coculture system or a stroma-free expansion system. Primary CB CD34+ cells or CD34+ cells expanded in either culture system demonstrated a similar ability to engraft. However, the MRP of expanded grafts simultaneously injected with primary CB cells was uniformly inferior to primary CB cells. CD34+ cell grafts expanded in the stroma-free system, furthermore, outcompeted CD34+ cells expanded using the PMVEC coculture system. The triple HLA-mismatched SCID-hu model represents a novel in vivo stem cell assay system that permits the direct demonstration of the functional consequences of ex vivo HSC expansion and ontogeny-related differences in HSCs.
VCAM-1 has a tissue-specific role in mediating interleukin-4–induced eosinophil accumulation in rat models: evidence for a dissociation between endothelial-cell VCAM-1 expression and a functional role in eosinophil migration
Authors: Larbi Karen Y. , Allen Andrew R. , Tam Frederick W. K. , Haskard Dorian O. , Lobb Roy R. , Silva Patricia M. R. , Nourshargh Sussan
Published: October 2019

Eosinophil accumulation has been associated with the pathogenesis of numerous allergic inflammatory disorders. Despite the great interest in this response, many aspects of eosinophil accumulation remain unknown. This is particularly true with respect to tissue-specific mechanisms that may regulate the accumulation of eosinophils in different organs. This study addressed this issue by investigating and comparing the roles of α4-integrins and vascular cell adhesion molecule 1 (VCAM-1) adhesion pathways in interleukin 4 (IL-4)–induced eosinophil accumulation in 2 different rat models of inflammation, namely pleural and cutaneous inflammation. Similar to our previous findings in studies in rat skin, locally administered IL-4 induced a time- and dose-dependent accumulation of eosinophils in rat pleural cavities, a response that was associated with generation of the chemokine eotaxin. The IL-4–induced eosinophil accumulation in skin and pleural cavities was totally inhibited by an antirat α4-integrins monoclonal antibody (mAb) (TA-2). In contrast, whereas an antirat VCAM-1 mAb (5F10) totally blocked the response in skin, IL-4–induced eosinophil accumulation in rat pleural cavities was not affected by VCAM-1 blockade. A radiolabeled mAb technique demonstrated that endothelial-cell VCAM-1 expression was induced in response to IL-4 in both skin and pleural membrane. The results indicate that although endothelial-cell VCAM-1 is present in skin and pleura, a functional role for it in IL-4–induced eosinophil accumulation was evident only in skin. These findings suggest the existence of tissue-specific adhesive mechanisms in regulating leukocyte migration in vivo and demonstrate a dissociation between VCAM-1 expression and eosinophil accumulation.
Lymphoproliferative disease of granular T lymphocytes presenting as aplastic anemia
Authors: Go Ronald S. , Tefferi Ayalew , Li Chin-Yang , Lust John A. , Phyliky Robert L.
Published: October 2019

Lymphoproliferative disease of granular T lymphocyte (T-LDGL), also known as T-cell large granular lymphocyte leukemia, is a clonal disorder of cytotoxic T lymphocytes that is clinically manifested as chronic neutropenia and anemia. Association with autoimmune disorders is common. In 9 patients, T-LDGL is reported as presenting as aplastic anemia. The clinical characteristics were similar to acquired aplastic anemia. Morphologic evidence of increased granular lymphocytes in the peripheral blood and an excess of CD3+/CD8+/CD57+ cells in the bone marrow were found in most cases. Cyclophosphamide was ineffective, but noncytotoxic immunosuppressive agents generally produced a good response. After a median follow-up of 49 months, 5 patients had died from the disease or related complications. Median survival was 40 months. Aplastic anemia can be a presenting manifestation of T-LDGL, and T-LDGL should be considered in the differential diagnosis of acquired aplastic anemia.
Spontaneous remission of granulocyte colony-stimulating factor–associated leukemia in a child with severe congenital neutropenia
Authors: Jeha Sima , Chan Ka Wah , Aprikyan Andrew G. , Hoots W. Keith , Culbert Steven , Zietz Hallie , Dale David C. , Albitar Maher
Published: October 2019

Leukemia is observed with increased frequency in patients with severe congenital neutropenia (SCN). In the past decade, recombinant human granulocyte colony-stimulating factor (rh G-CSF) has prolonged the survival of patients with SCN increasingly reported to have leukemias. In this communication acute myelogenous leukemia (AML) associated with a mutation of the G-CSF receptor (G-CSF-R) developed in a patient with SCN maintained on long-term G-CSF therapy. The blast count in the blood and bone marrow fell to undetectable levels twice on withholding G-CSF and without chemotherapy administration, but the mutant G-CSF-R was detectable during this period. The patient subsequently underwent successful allogeneic bone marrow transplantation. After transplantation, the patient's neutrophil elastase (ELA-2) mutation and G-CSF-R mutation became undetectable by polymerase chain reaction. This report provides novel insights on leukemia developing in congenital neutropenia.
Level of minimal residual disease after consolidation therapy predicts outcome in acute myeloid leukemia
Authors: Venditti Adriano , Buccisano Francesco , Del Poeta Giovanni , Maurillo Luca , Tamburini Anna , Cox Christina , Battaglia Alessandra , Catalano Gianfranco , Del Moro Beatrice , Cudillo Laura , Postorino Massimiliano , Masi Mario , Amadori Sergio
Published: October 2019

We used flow cytometry to quantify minimal residual disease (MRD) in 56 patients with acute myeloid leukemia (AML) expressing a leukemia-associated phenotype. Thirty-four patients aged 18 to 60 years were entered into the AML-10 protocol (induction, consolidation, and autologous stem-cell transplantation [ASCT]), whereas 22 patients older than 60 years received the AML-13 protocol (induction, consolidation, and consolidation II). After induction, the level of MRD that was best associated with treatment outcome was 4.5 × 10−4 residual leukemic cells. However, the outcome in patients with at least 4.5 × 10−4 cells (n = 26) was not significantly different from that in patients with fewer leukemic cells (n = 30); there were 15 (58%) relapses in the first group and 12 (40%) relapses in the second. After consolidation, the most predictive MRD cutoff value was 3.5 × 10−4cells: 22 patients had an MRD level of 3.5 × 10−4 cells or higher and 17 (77%) of these patients had relapse, compared with 5 of 29 patients (17%) with lower MRD levels (P < .001). An MRD level of 3.5 × 10−4 cells or higher after consolidation was significantly correlated with poor or intermediate-risk cytogenetic findings, a multidrug resistance 1 (MDR1) phenotype, short duration of overall survival, and short duration of relapse-free survival (P = .014, .031, .00022, and .00014, respectively). In multivariate analysis, this MRD status was significantly associated with a high frequency of relapse (P < .001) and a short duration of overall (P = .025) and relapse-free survival (P = .007). ASCT did not alter the prognostic effect of high MRD levels after consolidation: the relapse rate after transplantation was 70%. Thus, we found that an MRD level of 3.5 × 10−4 cells or higher at the end of consolidation strongly predicts relapse and is significantly associated with an MDR1 phenotype and intermediate or unfavorable cytogenetic findings.
Molecular analysis of 9 new families with chronic granulomatous disease caused by mutations in CYBA, the gene encoding p22phox
Authors: Rae Julie , Noack Deborah , Heyworth Paul G. , Ellis Beverly A. , Curnutte John T. , Cross Andrew R.
Published: October 2019

Chronic granulomatous disease is a rare inherited disorder caused by nonexistent or severely decreased phagocyte superoxide production that results in a severe defect in host defense and consequent predisposition to microbial infection. The enzyme responsible for generating the superoxide, NADPH oxidase, involves at least 5 protein components. The absence of, or a defect in, any 1 of 4 of these proteins (p22phox, p47phox, p67phox, or gp91phox) gives rise to the known types of chronic granulomatous disease. One of the rarest forms of the disease is due to defects in the CYBA gene encoding p22phox, which together with gp91phox forms flavocytochromeb558, the catalytic core of NADPH oxidase. To date, only 9 kindreds with p22phoxdeficiency have been described in the literature comprising 10 mutant alleles. Four polymorphisms in the CYBA gene have also been reported. Here we describe 9 new, unrelated kindreds containing 12 mutations, 9 of which are novel. In addition, we report 3 new polymorphisms. The novel mutations are (a) deletion of exons 2 and 3, (b) a missense mutation in exon 3 (T155→C), (c) a splice site mutation at the 5′ end of intron 3, (d) a missense mutation in exon 2 (G74→T), (e) a nonsense mutation in exon 1 (G26→A), (f) a missense mutation in exon 4 (C268→T), (g) a frameshift in exon 3 due to the insertion of C at C162, (h) a nonsense mutation in exon 2 (G107→A), and (i) a missense mutation in exon 2 (G70→A).
Pathologic gene expression in Gaucher disease: up-regulation of cysteine proteinases including osteoclastic cathepsin K
Authors: Moran Mary Teresa , Schofield J. Paul , Hayman Alison R. , Shi Guo-Ping , Young Elisabeth , Cox Timothy M.
Published: October 2019

Deficiency of lysosomal acid β-glucosidase induces glycolipid storage in the macrophages of Gaucher disease but the pathways of multisystem tissue injury and destruction are unknown. To investigate the cognate molecular pathology of this inflammatory disorder, genes that were differentially expressed in spleen samples from a patient with Gaucher disease (Gaucher spleen) were isolated. Of 64 complementary DNA (cDNA) fragments sequenced from an enriched Gaucher cDNA library, 5 encode lysosomal proteins (cathepsins B, K, and S, α-fucosidase, and acid lipase), 10 encode other known proteins, and 2 represent novel sequences from human macrophage cell lines. Transcript abundance of the cathepsins, novel genes, pulmonary and activation-regulated chemokine (PARC), and NMB, a putative tumor suppressor gene, was greatly increased. Immunoblotting showed increased mature forms of all 3 cathepsins found in samples of Gaucher spleens. Immunofluorescence microscopy showed strong cathepsin B and K reactions in sinusoidal endothelium and Gaucher cells. The respective means, plus or minus SD, of cathepsin B, K, and S activities were 183 ± 35, 97 ± 39, and 91 ± 45 nmol/min/mg protein in 4 Gaucher spleens, and 26 ± 4, 10.5 ± 2, and 4.0 ± 2.1 nmol/min/mg protein in 3 control spleens. Plasma cathepsin B, K, and S activities were also elevated in Gaucher disease plasma (P < .001), but compared with control plasma samples, neither cathepsin B nor K activities were significantly elevated in 8 patients with nonglycosphingolipid lysosomal storage diseases or in 9 patients with other glycosphingolipidoses, which suggests disease specificity. All 3 cathepsin activities were increased 2-fold to 3-fold in Gaucher sera compared with control sera. In all 6 patients treated by enzyme replacement for 16-22 months, serum cathepsin activities decreased significantly (P < .01). Longitudinal studies confirmed the progressive reduction of proteinase activities during imiglucerase therapy but in 3 Gaucher patients with mild disease not so treated, serum cathepsin activities remained constant or increased during follow-up. Enhanced expression of cysteine proteinases may promote tissue destruction. Moreover, the first identification of aberrant cathepsin K expression in hematopoietic tissue other than osteoclasts implicates this protease in the breakdown of the matrix that characterizes lytic bone lesions in Gaucher disease.
Class I–unrestricted noncytotoxic anti–HTLV-I activity of CD8+ T cells
Authors: Moriuchi Masako , Moriuchi Hiroyuki
Published: October 2019

Although it is widely believed that viral clearance is mediated principally by the destruction of infected cells by cytotoxic T cells, noncytolytic antiviral activity of CD8+ T cells may play a role in preventing the progression to disease in infections with immunodeficiency viruses and hepatitis B virus. We demonstrate here that (1) replication of human T-lymphotropic virus type I (HTLV-I) is more readily detected from CD8+ T-cell–depleted (CD8−) peripheral blood mononuclear cells (PBMCs) of healthy HTLV-I carriers than from unfractionated PBMCs, (2) cocultures of CD8− PBMCs with autologous or allogeneic CD8+ T cells suppressed HTLV-I replication, and (3) CD8+ T-cell anti-HTLV-I activity is not abrogated intrans-well cultures in which CD8+ cells are separated from CD8− PBMCs by a permeable membrane filter. These results suggest that class I-unrestricted noncytolytic anti–HTLV-I activity is mediated, at least in part by a soluble factor(s), and may play a role in the pathogenesis of HTLV-I infection.
Hemoglobin C associated with protection from severe malaria in the Dogon of Mali, a West African population with a low prevalence of hemoglobin S
Authors: Agarwal Aarti , Guindo Aldiouma , Cissoko Yacouba , Taylor James G. , Coulibaly Drissa , Koné Abdoulaye , Kayentao Kassoum , Djimde Abdoulaye , Plowe Christopher V. , Doumbo Ogobara , Wellems Thomas E. , Diallo Dapa
Published: October 2019

The malaria hypothesis proposes a survival advantage for individuals with hemoglobin variants in areas of endemicPlasmodium falciparum malaria. Hemoglobin C (HbC) is a possible example in West Africa, where this hemoglobin has a centric distribution with high frequencies among certain populations including the Dogon ethnic group. To test whether HbC is associated with protection from malaria, we performed a case-control study in the Dogon of Bandiagara, Mali. HbC was present in 68 of 391 (17.4%) of uncomplicated malaria control cases, whereas it was detected in only 3 of 67 cases (4.5%) of severe malaria (odds ratio [OR], 0.22;P = .01). Further, HbC was present in only 1 of 34 cases (2.9%) with cerebral manifestations, the most common presentation of severe malaria in this population (OR, 0.14; P = .03). Episodes of uncomplicated malaria and parasitemias (4800-205 050/μL) were identified in cases of homozygous HbC (HbCC), which indicates thatP falciparum parasites are able to efficiently replicate within HbCC erythrocytes in vivo. These findings suggest that HbC does not protect against infection or uncomplicated malaria but can protect against severe malaria in the Dogon population of Bandiagara, Mali. The data also suggest that the protective effect associated with HbC may be greater than that of HbS in this population.
Fetal and adult hemoglobin production during adult erythropoiesis: coordinate expression correlates with cell proliferation
Authors: Wojda Urszula , Noel Pierre , Miller Jeffery L.
Published: October 2019

The design and evaluation of therapies for the sickle cell and β-thalassemia syndromes rely on our understanding of hemoglobin accumulation during human erythropoiesis. Here we report direct measurements of hemoglobin composition and messenger RNA (mRNA) levels in cultured CD34+ cells and correlate those measurements with studies of freshly obtained bone marrow samples. Hemoglobin levels in differentiating cells were also compared with morphologic, immunophenotypic, and cell cycle assessments. A population of large preproerythroblasts was first identified within 24 hours and became the dominant population by day 5. The transition from proerythroblast to basophilic normoblast occurred later, from days 7 to 9, and correlated with a peak of 74.1% ± 3.9% of the cells in the S phase of cell cycle. Orthochromatic normoblasts were the dominant and final cell type by day 13. High-performance liquid chromatography–based quantitation of fetal (HbF) and adult (HbA) hemoglobin and real-time polymerase chain reaction globin mRNA quantitation demonstrated a coordinate rise in the accumulation of both proteins and mRNA among these developmentally staged populations. Quantitative analyses on freshly sorted bone marrow populations demonstrated a similar rising pattern with β-globin and HbA as the dominant species at both early and late stages of differentiation. We found no evidence for HbF dominant populations or switching during differentiation in adult cells. Instead, rapid increases in both HbF (heterocellular) and HbA (pancellular) content were observed, which coincided with the apex in cell cycling and the proerythroblast-basophilic normoblast transition. Based on these measurements, we conclude that HbF and HbA content are regulated with the rate of proliferation during adult erythropoiesis.
Emergency preparedness for infant and young child feeding in emergencies (IYCF-E): an Australian audit of emergency plans and guidance
Authors: Gribble Karleen , Peterson Mary , Brown Decalie
Published: October 2019

Background

Australia experiences a high incidence of natural emergencies and Australian governments have committed significant investment into emergency preparedness and response. Amongst the population groups most vulnerable to emergencies are infants and young children with their vulnerability centering around their specific food and fluid needs. For this reason, the World Health Assembly has urged all member states to develop and implement infant and young child feeding in emergency (IYCF-E) plans in line with international guidance. This study aimed to determine the degree to which Australia has complied with this direction by conducting an audit of Australian emergency plans and guidance.

Methods

Australian Federal, State/Territory and a sample of Local government emergency plans and guidance were located via web searches. Documents were searched for key words to identify content dealing with the needs of infants and young children. Plans and guidance were also searched for content dealing with the needs of animals as a comparison.

Results

While plans and guidance contained numerous pointers to the desirability of having plans that address IYCF-E, there was a dearth of planning at all levels of government for the needs of infants and young children. Guidance related to heat waves contained information that could prove dangerous to infants. No agency at Federal or State/Territory had designated responsibility for IYCF-E or children in general. This was in stark contrast to the situation of animals for which there was widespread and comprehensive planning at all levels of government with clear designation of organisational responsibility.

Conclusions

Lack of planning for IYCF-E in Australia places infants and young children at serious risk of adverse health consequences in emergencies. Australian Federal, State/Territory and Local governments need to take action to ensure that IYCF-E plans and guidance are developed and deployed in line with international standards. The pathway to successful integration of animal welfare plans provides a method for a similar integration of IYCF-E plans. Government health authorities are best placed to lead and be responsible for IYCF-E in Australia. National governments internationally should similarly take action to ensure that their youngest, most vulnerable citizens are protected in emergencies.
Evaluation of serological test of Zika in an endemic area of flavivirus in the Colombian Caribbean
Authors: Arrieta German , Mattar Salim , Villero-Wolf Yeneiris , Gomezcaceres Luty , Doria Amanda
Published: October 2019

The Zika virus (ZIKV) is an emerging flavivirus transmitted primarily through arthropods, endemic in Africa, Asia, and the Americas, and is considered a global threat by the World Health Organization.

Objective

To evaluate a commercial Zika virus test (IgG/IgM catalog number B815C, Biocan, Canada.

Methods

We evaluated 30 sera of patients diagnosed with Dengue, Leptospira, Malaria, Hantavirus, and Chikungunya. To establish the sensitivity of the test, two groups of sera were analyzed, the first one was patients with Zika RT-qPCR positive, and the second were patients RT-qPCR negative but with clinical suspicion of Zika.

Results

The specificity was of 23.3% (7/30), the sensitivity in acute patients with positive RT-qPCR was of 63.6%, the patients with clinical suspicion of Zika the sensitivity (IgM) was of 80% (n = 8/10). Overall sensitivity (IgM) of both groups was of 71.4% (15/21).

Conclusions

The test showed a low specificity to be used as a serological test in an endemic area of flavivirus infection.
New potentiometric sensors for methylphenidate detection based on host–guest interaction
Authors: AlRabiah Haitham , Abounassif Mohammed , Aljohar Haya I. , Mostafa Gamal Abdel-Hafiz
Published: October 2019

The study aims to develop simple, sensitive, and selective methods for detecting methylphenidate in its bulk, dosage form and human urine. Sensing materials include β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD), and 4-tertbutylcalix[8]arene as ionophores or electroactive materials have been used for construction of sensors 1, 2, and 3, respectively; Potassium tetrakis (4-chlorophenyl)borate (KTpClPB) as an ion additive was used and dioctyl phthalate as a plasticizer. The sensors displayed a fast, stable response over a wide concentration range of methylphenidate (8 × 10−6 M to 1 × 10−3 M) with 10−6 M detection limit over the pH range of 4–8. The developed sensors displayed a Near-Nernstian cationic response for methylphenidate at 59.5, 51.37, and 56.5 mV/decade for sensors β-CD, γ-CD, or 4-tertbutylcalix[8]arene respectively. Validation of the proposed sensors is supported by high accuracy, precision, stability, fast response, and long lifetimes, as well as selectivity for methylphenidate in the presence of different species. Sensitive and practical sensors for the determination of methylphenidate in bulk, in pharmaceutical forms and urine were developed and validated for routine laboratory use. The results were comparable to those obtained by HPLC method.
Correction to: Effects of challenge dose and inoculation route of the virulent Neospora caninum Nc-Spain7 isolate in pregnant cattle at mid-gestation
Authors: Vázquez Patricia , Osoro Koldo , Fernández Miguel , Román-Trufero Alicia , Regidor-Cerrillo Javier , Jiménez-Pelayo Laura , García-Sánchez Marta , Rojo-Montejo Silvia , Benavides Julio , Horcajo Pilar , Ortega-Mora Luis Miguel
Published: October 2019

In the original publication of this article [1], there are error in the Fig. 5, the “ml” should be replaced by “mL” (Fig. 5A) and “IFNγ” should be “IFN-γ” in Fig. 5A, B. The correct figure is below:
Financial incentives as a governmental tool to bridge the medical manpower gap between Israel’s center and periphery
Authors: Jacobson Eyal , Ezra Vered
Published: October 2019

One of the major health disparities between Israel’s center and periphery relates to the physician to population ratio. To overcome it, the Israeli government launched a financial incentive program in 2011, in an attempt to encourage physicians to work in the periphery and in specialties experiencing major shortages. A recent IJHPR study found that residents who choose to work in a peripheral institution gave more weight to the grant in their decision-making process than did residents from central institutions. This finding lends support to the rationale behind the government program and suggests that it is an effective means of achieving the desired goal.

This commentary details how the program was repeatedly adjusted during the 2011–2018 period, in light of changing needs. As financial and human resources are expected to remain scarce in the future, the program must continue to be constantly evaluated and adjusted in order to maintain its effectiveness.
Pembrolizumab in Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma
Authors: Armand Philippe , Rodig Scott , Melnichenko Vladimir , Thieblemont Catherine , Bouabdallah Kamal , Tumyan Gayane , Özcan Muhit , Portino Sergio , Fogliatto Laura , Caballero Maria D. , Walewski Jan , Gulbas Zafer , Ribrag Vincent , Christian Beth , Perini Guilherme Fleury , Salles Gilles , Svoboda Jakub , Zain Jasmine , Patel Sanjay , Chen Pei-Hsuan , Ligon Azra H. , Ouyang Jing , Neuberg Donna , Redd Robert , Chatterjee Arkendu , Balakumaran Arun , Orlowski Robert , Shipp Margaret , Zinzani Pier Luigi
Published: October 2019

PURPOSE

Patients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) have a poor prognosis, and their treatment represents an urgent and unmet need. Because PMBCL is associated with genetic aberrations at 9p24 and overexpression of programmed cell death-1 (PD-1) ligands (PD-L1), it is hypothesized to be susceptible to PD-1 blockade.

METHODS

In the phase IB KEYNOTE-013 (ClinicalTrials.gov identifier: NCT01953692 ) and phase II KEYNOTE-170 (ClinicalTrials.gov identifier: NCT02576990 ) studies, adults with rrPMBCL received pembrolizumab for up to 2 years or until disease progression or unacceptable toxicity. The primary end points were safety and objective response rate in KEYNOTE-013 and objective response rate in KEYNOTE-170. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Exploratory end points included association between biomarkers and pembrolizumab activity.

RESULTS

The objective response rate was 48% (7 complete responses; 33%) among 21 patients in KEYNOTE-013 and 45% (7 complete responses; 13%) among 53 patients in KEYNOTE-170. After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either study. No patient with complete response experienced progression, including 2 patients with complete response for at least 1 year off therapy. Treatment-related adverse events occurred in 24% of patients in KEYNOTE-013 and 23% of patients in KEYNOTE-170. There were no treatment-related deaths. Among 42 evaluable patients, the magnitude of the 9p24 gene abnormality was associated with PD-L1 expression, which was itself significantly associated with progression-free survival.

CONCLUSION

Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with rrPMBCL.
Efficacy, Safety, and Mechanistic Insights of Cotadutide, a Dual Receptor Glucagon-Like Peptide-1 and Glucagon Agonist
Authors: Parker Victoria E R , Robertson Darren , Wang Tao , Hornigold David C , Petrone Marcella , Cooper Aidan T , Posch Maximilian G , Heise Tim , Plum-Moerschel Leona , Schlichthaar Heike , Klaus Beate , Ambery Philip D , Meier Juris J , Hirshberg Boaz
Published: October 2019

Context

Cotadutide is a dual receptor agonist with balanced glucagon-like peptide-1 and glucagon activity.

Objective

To evaluate different doses of cotadutide and investigate underlying mechanisms for its glucose-lowering effects.

Design/setting

Randomized, double-blind, phase 2a study conducted in 2 cohorts at 5 clinical trial sites.

Patients

Participants were 65 adult overweight/obese patients with type 2 diabetes mellitus; 63 completed the study; 2 were withdrawn due to AEs.

Intervention

Once-daily subcutaneous cotadutide or placebo for 49 days. Doses (50–300 µg) were uptitrated weekly (cohort 1) or biweekly (cohort 2).

Main outcome measures

Co-primary end points (cohort 1) were percentage changes from baseline to end of treatment in glucose (area under the curve from 0 to 4 hours [AUC0–4h]) post–mixed-meal tolerance test (MMTT) and weight. Exploratory measures included postprandial insulin and gastric emptying time (GET; cohort 2).

Results

Patients received cotadutide (cohort 1, n = 26; cohort 2, n = 20) or placebo (cohort 1, n = 13; cohort 2, n = 6). Significant reductions were observed with cotadutide vs placebo in glucose AUC0–4h post MMTT (least squares mean [90% CI], −21.52% [−25.68, −17.37] vs 6.32% [0.45, 12.20]; P < 0.001) and body weight (−3.41% [−4.37, −2.44] vs −0.08% [−1.45, 1.28]; P = 0.002). A significant increase in insulin AUC0–4h post MMTT was observed with cotadutide (19.3 mU.h/L [5.9, 32.6]; P = 0.008) and GET was prolonged on day 43 with cotadutide vs placebo (t½: 117.2 minutes vs −42.9 minutes; P = 0.0392).

Conclusion

These results suggest that the glucose-lowering effects of cotadutide are mediated by enhanced insulin secretion and delayed gastric emptying.

Trial Registration

ClinicalTrials.gov, NCT03244800.
Activation of Notch Signaling by Oocytes and Jag1 in Mouse Ovarian Granulosa Cells
Authors: Hubbard Nisan , Prasasya Rexxi D , Mayo Kelly E
Published: October 2019

The Notch pathway plays diverse and complex roles in cell signaling during development. In the mammalian ovary, Notch is important for the initial formation and growth of follicles, and for regulating the proliferation and differentiation of follicular granulosa cells during the periovulatory period. This study seeks to determine the contribution of female germ cells toward the initial activation and subsequent maintenance of Notch signaling within somatic granulosa cells of the ovary. To address this issue, transgenic Notch reporter (TNR) mice were crossed with Sohlh1-mCherry (S1CF) transgenic mice to visualize Notch-active cells (EGFP) and germ cells (mCherry) simultaneously in the neonatal ovary. To test the involvement of oocytes in activation of Notch signaling in ovarian somatic cells, we ablated germ cells using busulfan, a chemotherapeutic alkylating agent, or investigated KitWv/Wv (viable dominant white-spotting) mice that lack most germ cells. The data reveal that Notch pathway activation in granulosa cells is significantly suppressed when germ cells are reduced. We further demonstrate that disruption of the gene for the Notch ligand Jag1 in oocytes similarly impacts Notch activation and that recombinant JAG1 enhances Notch target gene expression in granulosa cells. These data are consistent with the hypothesis that germ cells provide a ligand, such as Jag1, that is necessary for activation of Notch signaling in the developing ovary.
Appropriation, Common Property, the Inappropriable:
Authors: Brancaccio Francesco
Published: October 2019

This essay will show what are some of the qualifying characteristics of the theoretical construction of the law of the common. It will be divided into two parts. In the first part, I will review some of the main structural modifications that affected modern law with the advent of cognitive capitalism and digital platforms, in particular following the creation of the Internet of Things and cloud computing. In the second part, I will consider the pars construens of the law of the common, reflecting on the possibility of giving new conceptual meaning to the logic of appropriation and common property in the sense of it being inappropriable. In the end, I will propose that the inappropriability is an alternative to the conceptual duo of sovereignty and property.
Accuracy of fruit-fly eclosion rhythms evolves by strengthening circadian gating rather than developmental fine-tuning
Authors: Varma Vishwanath , Krishna Shambhavi , Srivastava Manishi , Sharma Vijay Kumar , Sheeba Vasu
Published: October 2019

Fruit flies (Drosophila melanogaster) eclose from their pupae mainly around dawn. The timing of eclosion is thought to confer adaptive benefits to the organisms and thus shows remarkable accuracy. However, it is not clear what factors are involved in the evolution of such accuracy in natural populations. In this study, we examined the relative contributions of gating of eclosion by the circadian clock versus clock-independent developmental rates and light-induced responses in the eclosion phenotype exhibited by fly populations that have evolved greater accuracy in eclosion rhythms compared to controls. We compared variation in timing of transitions between early developmental stages (pupariation and pigmentation), overall development time under constant light conditions – where circadian clocks are dysfunctional – and eclosion profiles when developmental rate was manipulated using different larval densities in selected and control stocks. Our results showed that stocks that have evolved greater accuracy of eclosion rhythms due to artificial selection do not show reduced individual variation in pupariation and pigmentation time compared to controls, though they do exhibit lower variation in eclosion time. Selected stocks also did not show lower variation in eclosion time under constant light conditions in contrast to the greater accuracy seen under light-dark cycles. Moreover, manipulations of developmental rate by varying larval density and inducing eclosion by changing onset of light phase did not alter the eclosion profile of selected stocks as much as it did controls, since selected stocks largely restricted eclosion to the daytime. These results suggest that fly populations selected for greater accuracy have evolved accurate eclosion rhythms primarily by strengthening circadian gating of eclosion rather than due to fine-tuning of clock-independent developmental processes.

This article has an associated First Person interview with the first author of the paper.