bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of Jak2 tyrosine kinase by protein kinase C during macrophage differentiation of IL-3–dependent myeloid progenitor cells
Authors: Kovanen Panu E. , Junttila Ilkka , Takaluoma Kati , Saharinen Pipsa , Valmu Leena , Li Weiqun , Silvennoinen Olli
Published: October 2019

Differentiation of macrophages from myeloid progenitor cells depends on a discrete balance between cell growth, survival, and differentiation signals. Interleukin-3 (IL-3) supports the growth and survival of myeloid progenitor cells through the activation of Jak2 tyrosine kinase, and macrophage differentiation has been shown to be regulated by protein kinase C (PKC). During terminal differentiation of macrophages, the cells lose their mitogenic response to IL-3 and undergo growth arrest, but the underlying signaling mechanisms have remained elusive. Here we show that in IL-3–dependent 32D myeloid progenitor cells, the differentiation-inducing PKC isoforms PKC- and PKC-δ specifically caused rapid inhibition of IL-3–induced tyrosine phosphorylation. The target for this inhibition was Jak2, and the activation of PKC by 12-O-tetradecanoyl-phorbol-13-acetate treatment also abrogated IL-3–induced tyrosine phosphorylation of Jak2 in Ba/F3 cells. The mechanism of this regulation was investigated in 32D and COS7 cells, and the inhibition of Jak2 required catalytic activity of PKC-δ and involved the phosphorylation of Jak2 on serine and threonine residues by the associated PKC-δ. Furthermore, PKC-δ inhibited the in vitro catalytic activity of Jak2, indicating that Jak2 was a direct target for PKC-δ. In 32D cells, the inhibition of Jak2 either by PKC-δ, tyrosine kinase inhibitor AG490, or IL-3 deprivation caused a similar growth arrest. Reversal of PKC-δ–mediated inhibition by the overexpression of Jak2 promoted apoptosis in differentiating 32D cells. These results demonstrate a PKC-mediated negative regulatory mechanism of cytokine signaling and Jak2, and they suggest that it serves to integrate growth-promoting and differentiation signals during macrophage differentiation.
Endotoxin and thrombin elevate rodent endothelial cell protein C receptor mRNA levels and increase receptor shedding in vivo
Authors: Gu Jian-Ming , Katsuura Yasuhiro , Ferrell Gary L. , Grammas Paula , Esmon Charles T.
Published: October 2019

The endothelial cell protein C receptor (EPCR) facilitates protein C activation by the thrombin-thrombomodulin complex. Protein C activation has been shown to be critical to the host defense against septic shock. In cell culture, tumor necrosis factor- (TNF-) down-regulates EPCR expression, raising the possibility that EPCR might be down-regulated in septic shock. We examined EPCR mRNA and soluble EPCR levels in mice and rats challenged with lethal dose 95 levels of endotoxin. Toxic doses of TNF- failed to alter EPCR mRNA levels in mice. Rather than EPCR mRNA levels falling in response to endotoxin, as predicted from cell-culture experiments, they rose approximately 3-fold 6 hours after exposure to endotoxin before returning toward baseline levels at 24 hours after exposure. Soluble EPCR levels rose approximately 4-fold. Infusion of hirudin, a specific thrombin inhibitor, before endotoxin exposure almost completely blocked the increase in EPCR mRNA and soluble EPCR. Consistent with the idea that the responses were mediated by thrombin, thrombin infusion (5 U/kg of body weight for 3 hours) resulted in an approximately 2-fold increase in EPCR mRNA and soluble EPCR. Incubation of rat endothelial cells with thrombin or murine protease-activated receptor 1 agonist peptide resulted in a 2-fold increase in EPCR mRNA. These results indicate that thrombin plays a major role in up-regulating EPCR mRNA and shedding in vivo.
Hypofibrinogenemia in an individual with 2 coding (γ82 A→G and Bβ235 P→L) and 2 noncoding mutations
Authors: Brennan Stephen O. , Fellowes Andrew P. , Faed James M. , George Peter M.
Published: October 2019

We investigated the molecular basis of hypofibrinogenemia in a man with a normal thrombin clotting time. Protein analysis indicated equal plasma expression of 2 different Bβ alleles, and DNA sequencing confirmed heterozygosity for a new Bβ235 P→L mutation. Protein analysis also revealed a novel γD chain, present at a ratio of 1:2 relative to the γA chain. Mass spectrometry indicated a 14 d decrease in the γD-chain mass, and DNA sequencing showed this was caused by a novel γ82 A→G substitution. DNA sequencing established heterozygosity for 2 further mutations: T→C in intron 4 of the A gene and A→C in the 3′ noncoding region of the Bβ gene. Studies on the man's daughter, together with plasma expression levels, discounted both the A and Bβ mutations as the cause of the low fibrinogen, suggesting that the γ82 mutation caused the hypofibrinogenemia. This was supported by analysis of 31 normal controls in whom the Bβ mutations were found at polymorphic levels, with an allelic frequency of 5% for the Bβ235 mutation and 42% for the Bβ 3′ untranslated mutation. The γ82 mutation was, however, unique to the propositus. Residue γ82 is located in the triple helix that separates the E and D domains, and aberrant packing of the helices may explain the decreased fibrinogen concentration.
Vaccination of patients with chronic myelogenous leukemia with bcr-abl oncogene breakpoint fusion peptides generates specific immune responses
Authors: Pinilla-Ibarz J. , Cathcart K. , Korontsvit T. , Soignet S. , Bocchia M. , Caggiano J. , Lai L. , Jimenez J. , Kolitz J. , Scheinberg D. A.
Published: October 2019

Chronic myelogenous leukemia (CML) presents a unique opportunity to develop therapeutic strategies using vaccination against a truly tumor-specific antigen that is also the oncogenic protein required for neoplasia. CML is characterized by the t(9;22) that results in the bcr-abl fusion oncogene and in the expression of a chimeric protein product p210. Previously we have shown that peptides derived from amino acid sequences crossing the b3a2 fusion breakpoint in p210 elicit class I restricted cytotoxic T lymphocytes and class II responses, respectively, in vitro. Such sequences may thus comprise absolutely tumor-specific antigens in a peptide-based vaccine. We evaluated the safety and immunogenicity of a multidose, bcr-abl breakpoint peptide vaccine in 12 adults with chronic-phase CML. Cohorts of 3 patients each received either 50 μg, 150 μg, 500 μg, or 1500 μg total peptide mixed with 100 μg QS-21 as an immunological adjuvant. Delayed-type hypersensitivity (DTH), humoral responses, and unprimed ex vivo autologous proliferation (3H-thymidine incorporation) and cytotoxicity (chromium-51 release) responses were measured. All 68 vaccinations were well tolerated without significant adverse effects. In 3 of the 6 patients treated at the 2 highest dose levels of vaccine, peptide-specific, T-cell proliferative responses (n = 3) and/or DTH responses (n = 2) were generated that lasted up to 5 months after vaccination. Cytotoxic T lymphocytes have not been identified. In conclusion, a tumor-specific, bcr-abl derived peptide vaccine can be safely administered to patients with chronic-phase CML and can elicit a bcr-abl peptide-specific immune response despite the presence of active disease in these patients and approximately 1012 leukemia cells.
Evidence that tristetraprolin is a physiological regulator of granulocyte-macrophage colony-stimulating factor messenger RNA deadenylation and stability
Authors: Carballo Ester , Lai Wi S. , Blackshear Perry J.
Published: October 2019

Deficiency of tristetraprolin (TTP), the prototype of the CCCH zinc finger proteins, results in a complex inflammatory syndrome in mice. Most aspects of the syndrome are secondary to excess circulating tumor necrosis factor (TNF)–, a consequence of increased stability of TNF- messenger RNA (mRNA) in TTP-deficient macrophages. TTP can bind directly to the AU-rich element in TNF- mRNA, increasing its lability. Here we show that TTP deficiency also results in increased cellular production of granulocyte-macrophage colony–stimulating factor (GM-CSF) and increased stability of its mRNA, apparently secondary to decreased deadenylation. Similar findings were observed in mice also lacking both types of TNF- receptors, excluding excess TNF- production as a cause of the increased GM-CSF mRNA levels and stability. TTP appears to be a physiological regulator of GM-CSF mRNA deadenylation and stability.
Deletion of 13q14 remains an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization
Authors: Zojer Niklas , Königsberg Robert , Ackermann Jutta , Fritz Elke , Dallinger Susanne , Krömer Elisabeth , Kaufmann Hannes , Riedl Lucia , Gisslinger Heinz , Schreiber Susanne , Heinz Renate , Ludwig Heinz , Huber Heinz , Drach Johannes
Published: October 2019

Interphase fluorescence in situ hybridization (FISH) studies of chromosomal region 13q14 were performed to investigate the incidence and clinical importance of deletions in multiple myeloma (MM). Monoallelic deletions of the retinoblastoma-1 (rb-1) gene and the D13S319 locus were observed in 48 of 104 patients (46.2%) and in 28 of 72 (38.9%) patients, respectively, with newly diagnosed MM. FISH studies found that 13q14 was deleted in all 17 patients with karyotypic evidence of monosomy 13 or deletion of 13q but also in 9 of 19 patients with apparently normal karyotypes. Patients with a 13q14 deletion were more likely to have stage III disease (P = .022), higher serum levels of β2-microglobulin (P = .059), and a higher percentage of bone marrow plasma cells (P = .085) than patients with a normal 13q14 status on FISH analysis. In patients with a deletion of 13q14, myeloma cell proliferation (Ki-67) was markedly increased (22.0% ± 6.9% compared with 15.6% ± 8.2% in patients without the deletion;P = .0008). Evaluation of bromodeoxyuridine incorporation in 5 patients revealed that both rb-1–deleted and rb-1–normal MM subpopulations were proliferative. The presence of a 13q14 deletion on FISH analysis was associated with a significantly lower rate of response to conventional-dose chemotherapy (40.8% compared with 78.6%; P = .009) and a shorter overall survival (24.2 months compared with > 60 months; P < .005) than in patients without the deletion. Multivariate analysis of prognostic factors confirmed the independent predictive value of 13q14 deletions for shortened survival. In conclusion, deletions of 13q14 are frequently detected by interphase FISH in patients with newly diagnosed MM, correlate with increased proliferative activity, and represent an independent adverse prognostic feature in MM.
Antilymphocyte globulin, cyclosporine, prednisolone, and granulocyte colony-stimulating factor for severe aplastic anemia: an update of the GITMO/EBMT study on 100 patients
Authors: Bacigalupo A. , Bruno B. , Saracco P. , Di Bona E. , Locasciulli A. , Locatelli F. , Gabbas A. , Dufour C. , Arcese W. , Testi G. , Broccia G. , Carotenuto M. , Coser P. , Barbui T. , Leoni P. , Ferster A.
Published: October 2019

One hundred consecutive patients with severe aplastic anemia (SAA) received horse antilymphocyte globulin (ALG), cyclosporin A (CyA), 6-methylprednisolone (6Mpred), and granulocyte colony-stimulating factor (G-CSF) as first-line therapy. The median age was 16 years (range, 1-72 years) and median neutrophil count was 0.2 × 109/L (range, 0-0.5 × 109/L). Trilineage hematologic recovery (at a median interval of 96 days from treatment) was seen in 77 patients (48 complete, 29 partial) after 1 (n = 50) or more courses of ALG (n = 27). Of the 23 nonresponders, 11 patients died at a median interval of 83 days (range, 16-1132 days), 6 were considered treatment failures and underwent transplantation, and 6 were pancytopenic. Cytogenetic abnormalities were seen in 11% of patients, clonal hematologic disease in 8%, and relapse of marrow aplasia in 9%. The actuarial survival at 5 years was 87% (median follow-up 1424 days): 76% versus 98% for patients with neutrophil counts less than versus greater than 0.2 × 109/L (P = .001) and 88% versus 87% for patients aged less than versus more than 16 years (P = .8). The actuarial probability of discontinuing CyA was 38%. Patients who did not achieve a white blood cell (WBC) count of 5 × 109/L during G-CSF treatment have a low probability of responding (37%) and a high mortality rate (42%). This update confirms a high probability for SAA patients of becoming transfusion independent and of surviving after treatment with ALG, CyA, 6Mpred, and G-CSF, with a significant effect of neutrophil counts on outcome. Problems still remain, such as absent or incomplete responses, clonal evolution, relapse of the original disease, and cyclosporine dependence. Early transplantation, also from alternative donors, may be warranted in patients with poor WBC response to G-CSF.
Aberrant p15 promoter methylation in adult and childhood acute leukemias of nearly all morphologic subtypes: potential prognostic implications
Authors: Wong Ivy H. N. , Ng Margaret H. L. , Huang Dolly P. , Lee Joseph C. K.
Published: October 2019

We prospectively analyzed p15 and p16 promoter methylation patterns using methylation-specific polymerase chain reaction (PCR) in patients with adult and childhood acute leukemias and studied the association of methylation patterns with chromosomal abnormalities and prognostic variables. In nearly all French-American-British leukemia subtypes, we found p15methylation in bone marrow or peripheral blood cells from 58% (46/79) of patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or acute biphenotypic leukemia (ABL). An identical alteration was detected in blood plasma from 11 of 12 of these patients (92%). We also demonstrated for the first time concomitant p16and p15 methylation in 22% (8/37) of adults with AML or ALL, exclusively in those with M2, M4, or L2 subtypes. According to cytogenetic data from 35 patients with ALL, AML, or ABL, 82% (14/17) of those with unmethylated p15 alleles had normal karyotypes or hyperdiploidies associated with a favorable prognosis. Conversely, 44% (8/18) of patients with p15 methylation had chromosomal translocations, inversions, or deletions, suggesting an interplay of these abnormalities with p15 methylation. As a prognostic marker for disease monitoring, p15 methylation appears to be more widely applicable than BCR-ABL, AF4-MLL, andAML1-ETO transcripts, which were detectable in only 8% (4/48) of patients by reverse transcriptase-PCR. Thirty-nine of 43 blood samples (91%) sequentially collected from 12 patients with AML, ALL, or ABL showed p15 methylation status in excellent concordance with morphologic disease stage. Early detection of p15methylation at apparent remission or its acquisition during follow-up may prove valuable for predicting relapse. Overall survival of patients with p15 methylation was notably shortened among 38 adults with AML and 12 adults with ALL. Aberrant p15 methylation may have important prognostic implications for clinical monitoring and risk assessment.
A secreted and LIF-mediated stromal cell–derived activity that promotes ex vivo expansion of human hematopoietic stem cells
Authors: Shih Chu-Chih , Hu Mickey C.-T. , Hu Jun , Weng Yehua , Yazaki Paul J. , Medeiros Jeffrey , Forman Stephen J.
Published: October 2019

The development of culture systems that facilitate ex vivo maintenance and expansion of transplantable hematopoietic stem cells (HSCs) is vital to stem cell research. Establishment of such culture systems will have significant impact on ex vivo manipulation and expansion of transplantable stem cells in clinical applications such as gene therapy, tumor cell purging, and stem cell transplantation. We have recently developed a stromal-based culture system that facilitates ex vivo expansion of transplantable human HSCs. In this stromal-based culture system, 2 major contributors to the ex vivo stem cell expansion are the addition of leukemia inhibitory factor (LIF) and the AC6.21 stromal cells. Because the action of LIF is indirect and mediated by stromal cells, we hypothesized that LIF binds to the LIF receptor on AC6.21 stromal cells, leading to up-regulated production of stem cell expansion promoting factor (SCEPF) and/or down-regulated production of stem cell expansion inhibitory factor (SCEIF). Here we demonstrate a secreted SCEPF activity in the conditioned media of LIF-treated AC6.21 stromal cell cultures (SCM-LIF). The magnitude of ex vivo stem cell expansion depends on the concentration of the secreted SCEPF activity in the SCM-LIF. Furthermore, we have ruled out the contribution of 6 known early-acting cytokines, including interleukin-3, interleukin-6, granulocyte macrophage colony-stimulating factor, stem cell factor, flt3 ligand, and thrombopoietin, to this SCEPF activity. Although further studies are required to characterize this secreted SCEPF activity and to determine whether this secreted SCEPF activity is mediated by a single factor or by multiple growth factors, our results demonstrate that stromal cells are not required for this secreted SCEPF activity to facilitate ex vivo stem cell expansion.
Two novel type 2N von Willebrand disease–causing mutations that result in defective factor VIII binding, multimerization, and secretion of von Willebrand factor
Authors: Allen Simon , Abuzenadah Adel M. , Blagg Joanna L. , Hinks Joanna , Nesbitt I. Mandy , Goodeve Anne C. , Gursel Turkiz , Ingerslev Jørgen , Peake Ian R. , Daly Martina E.
Published: October 2019

Two novel mutations, a T-to-C transition at nucleotide 2612 and a T-to-G transversion at nucleotide 3923 of the von Willebrand factor (vWF) complementary DNA, were detected by analysis of the vWF gene in DNA from members of 2 families with atypical von Willebrand disease. The T2612C transition predicts substitution of cysteine by arginine at amino acid position 788 (C788R), and the T3923G transversion predicts substitution of cysteine by glycine at position 1225 (C1225G) of pre-pro-vWF. The patients homozygous for the C788R and C1225G mutations both had a partial vWF deficiency (0.18 IU/mL and 0.07 IU/mL vWF antigen, respectively); vWF in plasma from patients homozygous for either the C788R or the C1225G mutation failed to bind factor VIII and lacked high molecular weight multimers. Recombinant (r) vWF molecules having the C788R or C1225G mutation were expressed in COS-7 cells. Both rvWF C788R and rvWF C1225G exhibited significantly impaired secretion and failed to bind factor VIII. Recombinant vWF C788R in COS-7 culture medium showed a severe reduction in high molecular weight multimers, whereas rvWF C1225G showed a very mild reduction in high molecular weight multimers when compared with wild-type rvWF.
Tumor-induced apoptosis of T lymphocytes: elucidation of intracellular apoptotic events
Authors: Gastman Brian R. , Johnson Daniel E. , Whiteside Theresa L. , Rabinowich Hannah
Published: October 2019

Our recent studies suggest that human squamous cell carcinoma of the head and neck (SCCHN) is capable of activating an intrinsic mechanism of programmed-cell death in interacting lymphocytes in situ and in vitro. The current study used Jurkat T-cell line as a model to investigate intracellular apoptotic events in T cells interacting with SCCHN. Apoptosis induced in T lymphocytes by tumor cells was in part Fas-mediated, since it was partially, but significantly, inhibited in the presence of anti-Fas ligand Ab or in Fas-resistant Jurkat cells. The synthetic caspase inhibitors, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-FMK) and N-benzyloxycarbonyl-Asp-glu-Val-Asp-fluoromethyl ketone (Z-DEVD-FMK), effectively blocked apoptosis of Jurkat cells co-incubated with SCCHN cell lines, suggesting the involvement of caspases in tumor-induced apoptosis of lymphocytes. Overexpression of CrmA, an inhibitor of caspase-1 and caspase-8, partially inhibited tumor-induced T-cell death. Caspase-8 and caspase-3 were identified as effector molecules in the execution of tumor-induced T-cell death, since the proform enzymes were processed into active subunits during co-incubation of T cells with tumor cells. Furthermore, co-incubation with tumor cells resulted in cleavage of poly(ADP-ribose) polymerase (PARP), a common caspase-3 substrate, and in cleavage of TcR-ζ chain, shown by us to be a T-cell specific caspase-3 substrate. Overexpression of Bcl-2 did not provide protection of T cells from SCCHN-induced DNA degradation. Instead, the Bcl-2 protein was cleaved in the target T cells during their co-incubation with tumor cells. These findings demonstrate that tumor cells can trigger in T lymphocytes caspase-dependent apoptotic cascades, which are not effectively protected by Bcl-2.
Nerve growth factor functions as a chemoattractant for mast cells through both mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways
Authors: Sawada Junko , Itakura Atsuko , Tanaka Akane , Furusaka Tohru , Matsuda Hiroshi
Published: October 2019

Despite being a well-characterized neurotrophic factor, nerve growth factor (NGF) influences survival, differentiation, and functions of mast cells. We investigated whether NGF was able to induce directional migration of rat peritoneal mast cells (PMCs). NGF clearly induced chemotactic movement of PMCs in a dose-dependent manner with the drastic morphological change and distribution of F-actin, which was completely blocked by pretreatment with Clostridium botulinumC2 toxin, an actin-polymerization inhibitor. Because PMCs constitutively express the NGF high-affinity receptor (TrkA) with a tyrosine kinase domain, we focused on downstream effectors in signaling cascades following the TrkA. NGF rapidly activated both mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K), and the addition of inhibitors specific for MAPK kinase and PI3K suppressed cell migration and these signals. In the coculture system with PMCs and fibroblasts, which produce biologically active NGF, directional migration of PMCs to fibroblasts was observed, and the addition of anti-NGF polyclonal antibodies significantly suppressed the migration of PMCs. These findings suggested that NGF initiated chemotactic movement of PMCs through both MAPK and PI3K signaling pathways following TrkA activation. Thus, locally produced NGF may play an important role in mast cell accumulation in allergic and nonallergic inflammatory conditions.
Transforming properties of chimeric TEL-JAK proteins in Ba/F3 cells
Authors: Lacronique Virginie , Boureux Anthony , Monni Richard , Dumon Stephanie , Mauchauffé Martine , Mayeux Patrick , Gouilleux Fabrice , Berger Roland , Gisselbrecht Sylvie , Ghysdael Jacques , Bernard Olivier A.
Published: October 2019

The involvement of the cytokine signaling pathway in oncogenesis has long been postulated. Recently, rearrangements of the gene encoding the tyrosine Janus kinase 2 (JAK2) have been reported in human leukemias indicating a direct JAK-signal transduction and activator of transcription (STAT)-mediated leukemic process. The leukemia-associated TEL-JAK2 fusion protein is formed by the oligomerization domain of the translocated ets leukemia (TEL) protein fused to the catalytic domain of JAK2. TEL-mediated oligomerization results in a constitutive tyrosine kinase activity that, in turn, is able to confer growth factor independence to the murine hematopoietic interleukin-3 (IL-3)-dependent Ba/F3 cell line. Results of the present study indicate that fusion proteins containing the oligomerization domain of TEL and the tyrosine kinase domains of Jak1, Jak2, JAK3, or TYK2 share similar properties and are able to efficiently substitute for the survival and mitogenic signals controlled by IL-3, without concomitant activation of the IL-3 receptor. Electrophoretic mobility shift assays demonstrated Stat5 as the only activated Stat factor in TEL-Jak2- and TEL-Jak1-expressing cells, whereas other Stats, namely Stat1 and Stat3, could be detected in TEL-JAK3-, TEL-TYK2-, and also in TEL-ABL-expressing Ba/F3 cells. High levels of expression of the Stat5-target genes pim-1, osm, and Cis were observed in all the cytokine-independent cell lines. Furthermore, the expression of a dominant negative form of Stat5A markedly interfered with the growth factor independence process mediated by TEL-Jak2 in Ba/F3 cells. Because the BCR-ABL and TEL-PDGFβR oncoproteins also activate Stat5, activation of this factor should be a crucial step in activated tyrosine kinase-mediated leukemogenesis.
Cytogenetic abnormalities in the myelodysplastic syndromes and occupational or environmental exposure
Authors: West R. R. , Stafford D. A. , White A. D. , Bowen D. T. , Padua R. A.
Published: October 2019

Patients with myelodysplastic syndromes (MDS) have high frequencies of cytogenetic abnormalities and evidence is accumulating of associations between exposure history and primary MDS. The objective of this article is to examine the relationship between histories of occupational or environmental exposure and presence of cytogenetic abnormalities. A case control study of MDS patients estimated lifetime exposure to more than 90 potential hazards in 400 age, sex, and area of residence matched patient and control pairs. A parallel cytogenetics study undertaken at time of diagnosis, independently of any knowledge of exposure history, identified 75 cytogenetically abnormal and 139 normal (186 not studied). Odds ratios of MDS patients and their matched controls were compared for 3 groups: cytogenetically abnormal, normal, and not known. The odds ratios for all exposures combined were possibly higher among cytogenetically abnormal 2.0 (95% confidence interval 0.8-5.9) than among normal 1.0 (0.6-1.8). This pattern was observed for exposure to semimetals, abnormal 4.0 (0.4-195.1) and normal 0.5 (0.1-1.0) and inorganic dusts, 1.6 (0. 6-3.8) and 0.4 (0.1-1.4) respectively. The pattern was principally in abnormalities in chromosomes 5 and 7. For organic chemicals and radiation, the odds ratios for both cytogenetically abnormal and normal were marginally raised: organic 1.8 (0.6-6.0) and 1.3 (0.6-2.9), respectively, and radiation 1.7 (0.5-5.6) and 1.3 (0.4-4.7) respectively. For radiation, abnormalities were mostly in chromosome 8. This study of association between exposures and cytogenetics in primary MDS complements those previously reported in secondary MDS and may provide some insight into pathogenetic mechanisms that lead to development of MDS.
c-Myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasome-mediated turnover
Authors: Bahram Fuad , von der Lehr Natalie , Cetinkaya Cihan , Larsson Lars-Gunnar
Published: October 2019

The c-myc proto-oncogene encodes a short-lived transcription factor that plays an important role in cell cycle regulation, differentiation and apoptosis. c-myc is often rearranged in tumors resulting in deregulated expression. In addition, mutations in the coding region of c-myc are frequently found in human lymphomas, a hot spot being the Thr58 phosphorylation site, a mutation shown to enhance the transforming capacity of c-Myc. It is, however, still unclear in what way this mutation affects c-Myc activity. Our results show that proteasome-mediated turnover of c-Myc is substantially impaired in Burkitt's lymphoma cells with mutated Thr58 or other mutations that abolish Thr58 phosphorylation, whereas endogenous or ectopically expressed wild type c-Myc proteins turn over at normal rates in these cells. Myc Thr58 mutants expressed ectopically in other cell types also exhibit reduced proteasome-mediated degradation, which correlates with a substantial decrease in their ubiquitination. These results suggest that ubiquitin/proteasome-mediated degradation of c-Myc is triggered by Thr58 phosphorylation revealing a new important level of control of c-Myc activity. Mutation of Thr58 in lymphoma thus escapes this regulation resulting in accumulation of c-Myc protein, likely as part of the tumor progression.
A novel family of PLAC8 motif-containing/PCR genes mediates Cd tolerance and Cd accumulation in rice
Authors: Wang Feijuan , Tan Haifeng , Han Jiahui , Zhang Yiting , He Xigeduleng , Ding Yanfei , Chen ZhiXiang , Zhu Cheng
Published: October 2019

Background

Cd is one of the highly toxic heavy metals to most organisms, including humans and plants, and Cd-contaminated rice from China has become a global food safety issue. The early prediction of OsPCR (the plant cadmium resistance protein) which contained a PLAC8 domain was related with the accumulation of Cd in rice. To further understand the biological function of the OsPCR genes on the Cd tolerance and Cd accumulation in rice, we used a low grain-Cd-accumulating rice (xiushui 11) and a high grain-Cd-accumulating rice (xiushui 110) varieties to analyze the relationship between the expression levels of the two most abundant expression genes (OsPCR1 and OsPCR3) and the Cd concentrations in different tissues at different growth periods during Cd stress, and transgenic experiments of OsPCR1 and OsPCR3 were carried out.

Results

OsPCR1 and OsPCR3 were closely related with Cd accumulation. Overexpression of OsPCR1 and OsPCR3 could not only increase the Cd tolerance, but also decrease the Cd accumulation obviously in different parts of the transgenic rice plants (especially in the rice grains), while the RNAi expression plants showed the opposite results.

Conclusions

These results indicate that OsPCR1 and OsPCR3 play critical roles in Cd accumulation in rice, which provides a theoretical basis for the safe production of rice.
Genomic analysis of the four ecologically distinct cactus host populations of Drosophila mojavensis
Authors: Allan Carson W. , Matzkin Luciano M.
Published: October 2019

Background

Relationships between an organism and its environment can be fundamental in the understanding how populations change over time and species arise. Local ecological conditions can shape variation at multiple levels, among these are the evolutionary history and trajectories of coding genes. This study examines the rate of molecular evolution at protein-coding genes throughout the genome in response to host adaptation in the cactophilicDrosophila mojavensis. These insects are intimately associated with cactus necroses, developing as larvae and feeding as adults in these necrotic tissues.Drosophila mojavensisis composed of four isolated populations across the deserts of western North America and each population has adapted to utilize different cacti that are chemically, nutritionally, and structurally distinct.

Results

High coverage Illumina sequencing was performed on three previously unsequenced populations ofD. mojavensis. Genomes were assembled using the previously sequenced genome ofD. mojavensisfrom Santa Catalina Island (USA) as a template. Protein coding genes were aligned across all four populations and rates of protein evolution were determined for all loci using a several approaches.

Conclusions

Loci that exhibited elevated rates of molecular evolution tend to be shorter, have fewer exons, low expression, be transcriptionally responsive to cactus host use and have fixed expression differences across the four cactus host populations. Fast evolving genes were involved with metabolism, detoxification, chemosensory reception, reproduction and behavior. Results of this study give insight into the process and the genomic consequences of local ecological adaptation.
The cost-effectiveness of incentive-based active case finding for tuberculosis (TB) control in the private sector Karachi, Pakistan
Authors: Hussain Hamidah , Mori Amani Thomas , Khan Aamir J. , Khowaja Saira , Creswell Jacob , Tylleskar Thorkild , Robberstad Bjarne
Published: October 2019

Background

In Asia, over 50% of patients with symptoms of tuberculosis (TB) access health care from private providers.These patients are usually not notified to the National TB Control Programs, which contributes to low notification rates in many countries.

Methods

From January 1, 2011 to December 31, 2012, Karachi’s Indus Hospital - a private sector partner to the National TB Programme - engaged 80 private family clinics in its catchment area in active case finding using health worker incentives to increase notification of TB disease. The costs incurred were estimated from the perspective of patients, health facility and the program providing TB services. A Markov decision tree model was developed to calculate the cost-effectiveness of the active case finding as compared to case detection through the routine passive TB centers. Pakistan has a large private health sector, which can be mobilized for TB screening using an incentivized active case finding strategy. Currently, TB screening is largely performed in specialist public TB centers through passive case finding. Active and passive case finding strategies are assumed to operate independently from each other.

Results

The incentive-based active case finding program costed USD 223 per patient treated. In contrast, the center based non-incentive arm was 23.4% cheaper, costing USD 171 per patient treated. Cost-effectiveness analysis showed that the incentive-based active case finding program was more effective and less expensive per DALY averted when compared to the baseline passive case finding as it averts an additional 0.01966 DALYs and saved 15.74 US$ per patient treated.

Conclusion

Both screening strategies appear to be cost-effective in an urban Pakistan context. Incentive driven active case findings of TB in the private sector costs less and averts more DALYs per health seeker than passive case finding, when both alternatives are compared to a common baseline situation of no screening.
Aryl hydrocarbon receptor modulates stroke-induced astrogliosis and neurogenesis in the adult mouse brain
Authors: Chen Wan-Ci , Chang Li-Hsin , Huang Shiang-Suo , Huang Yu-Jie , Chih Chun-Lien , Kuo Hung-Chih , Lee Yi-Hsuan , Lee I-Hui
Published: October 2019

Background

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor activated by environmental agonists and dietary tryptophan metabolites for the immune response and cell cycle regulation. Emerging evidence suggests that AHR activation after acute stroke may play a role in brain ischemic injury. However, whether AHR activation alters poststroke astrogliosis and neurogenesis remains unknown.

Methods

We adopted conditional knockout of AHR from nestin-expressing neural stem/progenitor cells (AHRcKO) and wild-type (WT) mice in the permanent middle cerebral artery occlusion (MCAO) model. WT mice were treated with either vehicle or the AHR antagonist 6,2′,4′-trimethoxyflavone (TMF, 5 mg/kg/day) intraperitoneally. The animals were examined at 2 and 7 days after MCAO.

Results

The AHR signaling pathway was significantly upregulated after stroke. Both TMF-treated WT and AHRcKO mice showed significantly decreased infarct volume, improved sensorimotor, and nonspatial working memory functions compared with their respective controls. AHR immunoreactivities were increased predominantly in activated microglia and astrocytes after MCAO compared with the normal WT controls. The TMF-treated WT and AHRcKO mice demonstrated significant amelioration of astrogliosis and microgliosis. Interestingly, these mice also showed augmentation of neural progenitor cell proliferation at the ipsilesional neurogenic subventricular zone (SVZ) and the hippocampal subgranular zone. At the peri-infarct cortex, the ipsilesional SVZ/striatum, and the hippocampus, both the TMF-treated and AHRcKO mice demonstrated downregulated IL-1β, IL-6, IFN-γ, CXCL1, and S100β, and concomitantly upregulated Neurogenin 2 and Neurogenin 1.

Conclusion

Neural cell-specific AHR activation following acute ischemic stroke increased astrogliosis and suppressed neurogenesis in adult mice. AHR inhibition in acute stroke may potentially benefit functional outcomes likely through reducing proinflammatory gliosis and preserving neurogenesis.
The effect of spinal manipulative therapy on heart rate variability and pain in patients with chronic neck pain: a randomized controlled trial
Authors: Galaasen Bakken Anders , Axén Iben , Eklund Andreas , O’Neill Søren
Published: October 2019

Background

Recent experimental research has suggested that spinal manipulative therapy (SMT) may reduce pain through modulation of the ascending pain signals and/or the central pain-regulating mechanisms. People with persistent neck pain (NP) have also been found to have disturbances in autonomic nervous system (ANS) regulation. A common way to study the ANS is to measure heart rate variability (HRV). It is not known whether deviations in HRV are related to changes in pain perception or to the treatment response to SMT.

Commonly, an individual in pain will experience pain reduction when exposed to a second pain stimulus, a mechanism known as conditioned pain modulation (CPM). Patients with persistent pain have been found to have a reduced CPM reaction. It is not known whether this is predictive of treatment response to SMT.

The aim of the study is to examine the effects of SMT on HRV and pain. Further, a secondary aim is to test whether a CPM test can be used to predict treatment response in a population of patients with recurrent and persistent NP.

Method/design

A multicentre randomized controlled clinical trial will be carried out in multidisciplinary primary care clinics. This setting is chosen to minimize bias resulting from patient preference for the treatment modality and provider.

The subjects are either self-referred or referred from other health care practitioners locally. The treatment modalities are two well-known interventions for NP; SMT and stretching exercises compared to stretching exercises alone.

HRV will be measured using a portable heart monitor. The subjective pain experience will be investigated by assessing pain intensity and the affective quality of pain. CPM will be measured with a standardized cold pressor test. Measurements will be performed three times during a 2-week treatment series.

Discussion

The study will utilize normal clinical procedures, which should aid the transferability and external validity of the results. The study will provide knowledge regarding the underlying mechanisms of the effects of SMT. Furthermore, the study will examine whether a CPM test is predictive of treatment outcome in a population of patients with recurrent and persistent NP.

Trial registration

ClinicalTrials.gov, NCT03576846. Registered on 3 July 2018.
Identification of significant proxy variable for the physiological status affecting salt stress-induced lipid accumulation in Chlorella sorokiniana HS1
Authors: Oh Seung Hwan , Chang Yong Keun , Lee Jay Hyung
Published: October 2019

Background

Current efforts on the optimization of the two-stage cultivation using stress-induced lipid accumulation have mostly focused only on the lipid induction stage. Although recent studies have shown that stress-induced lipid accumulation is affected by the physiological status of the cells harvested at the preceding cultivation stage, this issue has hardly been examined hitherto. Such a study needs to be carried out in a systematic way in order to induce lipid accumulation in a consistent and predictable manner with regard for variances seen at the cultivation stage.

Results

After a photoautotrophic cultivation of Chlorella sorokiniana HS1 in a modified BG11, harvested cells were re-suspended in the fresh medium, and then NaCl was added as the sole stress inducer with light illumination to induce additional accumulation of lipid. Effects of culture temperature on the lipid accumulation were analyzed by the Kruskal–Wallis test. From the microscopic observation, we had observed a definite increase in lipid body induced by the stress since the cell entered a stationary phase. A multiple linear regression model was developed so as to identify significant parameters to be included for the estimation of lipid induction. As a result, several key parameters at the end of cultivation, such as cell weight, total lipid content, chlorophyll a in a cell, and Fv/Fm, were identified as the important proxy variables for the cell’s physiological status, and the modeling accuracy was achieved by 87.6%. In particular, the variables related to Fv/Fm were shown to have the largest influence, accounting for 65.7% of the total variance, and the Fv/Fm had an optimal point of maximum induction at below its average. Clustering analysis using the K-means algorithm indicated that the algae which are 0.15 pg cell−1 or less in chlorophyll concentration, regardless of other conditions, had achieved high induction results.

Conclusion

Experimental results showed that it usually achieves high lipid induction after the cells naturally end their division and begin to synthesize lipid. The amount of lipid induction could be estimated by the selected proxy variables, and the estimation method can be adapted according to practical situations such as those with limited measurements.
The analysis of the Saltzman Collection of Peruvian dyes by high performance liquid chromatography and ambient ionisation mass spectrometry
Authors: Armitage Ruth Ann , Fraser Daniel , Degano Ilaria , Colombini Maria Perla
Published: October 2019

Yarn samples from the Saltzman Collection of Peruvian dyes were characterized by several different analytical techniques: high performance liquid chromatography with both diode array detection (HPLC-DAD) and electrospray ionisation with tandem mass spectrometry (HPLC-ESI-Q-ToF), direct analysis in real time (DART) mass spectrometry and paper spray mass spectrometry. This report serves primarily as a database of chemical information about the colorants in these dye materials for those studying ancient South American textiles and their colorants. We also provide a comparison of the results obtained by currently widespread HPLC techniques with those of two different ambient ionisation direct mass spectrometry methods to highlight the advantages and disadvantages of these approaches.
Classification of growth hormone idiopathic insufficiency: Clinical features and efficacy of therapy with growth hormone
Authors: Price D. A.
Published: October 2019

In 3,226 patients with idiopathic growth hormone (GH) deficiency included in the KIGS study, a comparative analysis of epidemiological factors and the effectiveness of treatment with recombinant GH depending on the presence or absence of birth trauma was performed. The relative frequency of gluteal presentation, instrumental AIDS in childbirth, reduced Apgar score, neonatal hypoglycemia and occurrence of microfallos was higher in the group with birth trauma, which was manifested later by more severe hypopituitarism and earlier manifestations of the disease. Both groups had almost the same reaction to GH therapy. A similar study was conducted in a group of children with GH deficiency in combination with empty Turkish saddle syndrome, septooptic dysplasia, cleft palate, neurosecretory dysfunction and secretion of biologically inactive GH. The comparative analysis was carried out with a group of children with idiopathic insufficiency of GH. Despite the differences in the clinical picture between the groups, the effectiveness of treatment of GH was the same. The study confirms the concept of multifactorial etiology of idiopathic gr insufficiency. Comparison with other groups of congenital insufficiency of GH indicates that complications in the perinatal period may occur secondary to hypopituitarism.
Effect of I-131 incorporation on male rat reproductive system and the dose-dependent effect
Authors: Tarasenko L. V. , Varga S. V. , Demchenko V. N. , Bolshova Ye. V. , Nosenko N. D. , Sinitsyn P. V. , Chaikovskaya L. V. , Reznikov A. G.
Published: October 2019

Radioactive 131Iwas injected in single doses 9.25, 37, and 92.5 kBq to prepubertal (30-day-old) male rats. Iodine incorporation in doses 37 and 92.5 kBq resulted in some functional changes in the reproductive system of mature rats: blood testosterone level increased, its hypothalamic aromatization intensified, and biologically active LH level in the blood dropped. Incorporation of 9.25 kBq of 131-I had no effect on male reproductive system. A possibility of direct injury to rat testicles by 131I incorporation is suggested.
Androgen-receptor activity in patients with false male hermaphroditism: a critical review of methods of investigation
Authors: Kasatkina E. P. , Samsonova L. N. , Kushlinsky N. Ye. , Lyakina L. T.
Published: October 2019

The paper is devoted to search for informative methods of examining patients with false male hermaphroditism which would permit assessment of androgen receptor activity in the early postnatal period and, hence, timely verify the testicular feminization syndrome and determine the desirable sex for upbringing the patient. With this aim in view specific binding of androgen receptors in the cytosol fraction of pubic skin biopsy specimens and sensitivity of androgen-dependent tissues to exogenously injected testosterone were studied in 60 patients aged 9 months to 14 years. The latter parameter was assessed by two methods: in response to parenteral depot-testosterone and to application of oily solution of testosterone propionate. Study of specific binding of androgen receptors in the cytosol fraction of pubic skin biopsy specimens was not informative for the diagnosis of the testicular feminization syndrome. The diagnostic value of investigating the sensitivity of androgen-dependent tissues to exogenous testosterone assessed by clinical signs (pigmentation of the scrotum, erection, and size of the penis) together with assessment of androgen receptor activity is satisfactory and does not depend on the mode of drug administration.
KRITIK METODOLOGI PENAFSIRAN BUCAILLISME ATAS AYAT-AYAT SAINS
Authors: Permono Ajar
Published: October 2019

Discourse on scientific theology is quite often lead to debate among scholars and scientists today. The central point of the debate is on the relationship between the Qur’an dan science, namely the Total Agreement, Partial Agreement and the Refuse Group. Bucaillism as representation the Total Agreement group has the view that the Quran besides functioning as a moral-ethical guideline and guidance is also the source of all the phenomena of science. This article to photograph what and how bucaillism, find the cause and do methodological criticisms on it. This research concludes that the tendency towards the progress of science becomes an important point in the progress of the civilization of Muslims. With the harmonization of science and religion, it can increase creativity and innovation in doing business in making discoveries. Qur’an which contains many creeds and moral-ethical and verses of science can be a guide for scientists in developing science and technology so that the benefit of humans and the environment is always maintained. Nevertheless, the argumentative basis in scientific research is not only based on the literal meaning of the text but leads to the moral-ethical content.Keyword: Bucaillism, Quran, Phenomena of Science
DAKWAH BERBASIS KEBUDAYAAN SEBAGAI UPAYA MEMBANGUN MASYARAKAT MADANI DALAM SURAT AL-NAHL: 125
Authors: Kurdi Alif Jabal
Published: October 2019

Islam has been present in Indonesia to bring change to a better direction. Islam is not directly accepted by the people of Indonesia. As a step of the initiative of Islamic missionaries in Indonesia, it uses an approach that deals with matters that are inherent in the everyday life of Indonesian society. One of the most effective approaches to spreading Islam is through culture. Indeed, what has been done by Indonesian Islamic preachers reflects the spirit of dakwah, which is recommended by Allah in his word (Q.S. al-Nahl: 125). As a contextualized form of the Rasulullah dakwah method, Islamic preachers in Indonesia have presented Islam really in its context as a religion, not as an Arabic cultural product, as it has recently been misunderstood by some. Through socio-historical-contextual approaches with linguistic analysis based on the interpretation of the scholar's linguistic and social use theory and the use of gratification theory introduced by Herbert Blumer and Elihu Katz, this paper will reveal the values and messages of practice preaching the Prophet to Arab society in his time linked to the practice of dakwah Ulama Indonesia so as to make people aware of the importance of culture in building a civil life, which through culture.Keywords: Dakwah, al-Nahl: 125, Civic Society