bluuebunny/crossref_metadata_2025 huggingface dataset:
α-Fibrinogen Thr312Ala polymorphism and venous thromboembolism
Authors: Carter Angela M. , Catto Andrew J. , Kohler Hans P. , Ariëns Robert A. S. , Stickland Max H. , Grant Peter J.
Published: October 2019

The A-fibrinogen Thr312Ala polymorphism, which occurs in a region involved in factor XIII (FXIII)-dependent cross-linking processes, is associated with poststroke mortality in subjects with atrial fibrillation, suggesting an influence either on intraatrial clot formation or embolization. We have determined the association of Thr312Ala with deep vein thrombosis (DVT) and pulmonary embolism (PE) and have assessed the interaction of Thr312Ala with the FXIII Val34Leu polymorphism in 122 patients with DVT, 99 patients with PE, and 254 healthy control subjects. The genotype distribution of patients with PE (TT = 49%, TA = 36%, AA = 15%), but not DVT (TT = 50%, TA = 42%, AA = 8%), differed significantly from healthy control subjects (TT = 60%, TA = 34%, AA = 6%, P = .02). A significant interaction of Thr312Ala and Val34Leu was also identified (P = .01), indicating an inverse association between Leu34 and Ala312. These results support the hypothesis that Thr312Ala alters FXIII-dependent cross-linking, making formed fibrin clot more susceptible to embolization.
Ligation of the CD44 adhesion molecule inhibits drug-induced apoptosis in human myeloid leukemia cells
Authors: Allouche Michèle , Charrad Rachida Sihem , Bettaieb Ali , Greenland Catherine , Grignon Cécile , Smadja-Joffe Florence
Published: October 2019

Adhesion molecules can improve hematopoietic cell survival; however, their role in leukemic cell resistance to drug-induced apoptosis is poorly documented. The CD44 adhesion molecule is strongly expressed on acute myeloid leukemia (AML) blasts. Using 2 myeloid cell lines, HL60 and NB4, evidence is presented that prior incubation with the CD44-specific monoclonal antibody (mAb) A3D8, reported to induce differentiation of AML blasts, significantly decreases apoptosis induced by 3 drugs used in AML chemotherapy: daunorubicin (DNR), mitoxantrone, and etoposide. In addition, in HL60 cells, CD44 ligation with A3D8 mAb fully abrogates the DNR-triggered generation of ceramide, a lipid second messenger involved in the DNR apoptotic signaling pathway. Moreover, results show that the A3D8 mAb and Bcl-2 additively inhibit DNR-induced apoptosis in HL60 cells overexpressing Bcl-2. These results suggest that, to eradicate AML blasts, the differentiation-inducing anti-CD44 mAb A3D8 should not be administered prior to apoptosis-inducing drugs.
α-Thalassemia resulting from a negative chromosomal position effect
Authors: Barbour Virginia M. , Tufarelli Cristina , Sharpe Jacqueline A. , Smith Zoe E. , Ayyub Helena , Heinlein Cynthia A. , Sloane-Stanley Jacqueline , Indrak Karel , Wood William G. , Higgs Douglas R.
Published: October 2019

To date, all of the chromosomal deletions that cause -thalassemia remove the structural  genes and/or their regulatory element (HS –40). A unique deletion occurs in a single family that juxtaposes a region that normally lies approximately 18-kilobase downstream of the human  cluster, next to a structurally normal -globin gene, and silences its expression. During development, the CpG island associated with the -globin promoter in the rearranged chromosome becomes densely methylated and insensitive to endonucleases, demonstrating that the normal chromatin structure around the -globin gene is perturbed by this mutation and that the gene is inactivated by a negative chromosomal position effect. These findings highlight the importance of the chromosomal environment in regulating globin gene expression.
The immunophenotype of 177 adults with acute myeloid leukemia: proposal of a prognostic score
Authors: Legrand Ollivier , Perrot Jean-Yves , Baudard Marion , Cordier Annie , Lautier Régine , Simonin Ghislaine , Zittoun Robert , Casadevall Nicole , Marie Jean-Pierre
Published: October 2019

In acute myeloid leukemia (AML) patients, a variety of clinical and biologic parameters, including phenotype, have been examined for potential value in predicting treatment response and survival. The European Group for the Immunological Classification of Leukaemias (EGIL) has proposed that AML be defined immunologically by the expression of 2 or more of the following myeloid markers: myeloperoxidase, CD13, CD33, CDw65, and CD117. With regard to this classification, the prognostic significance of 21 antigens taken separately and with immunophenotypic subgroups were evaluated and compared with other clinical and biological variables in 177 adult AML patients. None of the antigens tested were associated with treatment outcome. In contrast, patients with blasts disclosing a full expression of panmyeloid phenotype (defined by the expression of all 5 myeloid markers) had a higher complete remission rate (P < .0001) and differed significantly in disease-free survival (P = .02) and overall survival (P = .008) than patients whose cells expressed fewer than 5 of these markers. In multivariate analysis, only age, panmyeloid phenotype, performance status, and permeability glycoprotein activity influence treatment outcome. Cytogenetics was significant in univariate analysis but not in multivariate analysis, most likely because of the redundancy with panmyeloid phenotype and a higher sensitivity of immunophenotyping. Patients whose cells exhibit the panmyeloid phenotype appear to define a relatively homogeneous biological subset of AML. The 4 independent prognostic factors were used to create a prognostic score, defined by the number of factors present. This score permitted a stratification of patients with AML, thereby allowing for the consideration of innovative therapies to improve outcome in the poorer outcome groups.
In vivo generation of human dendritic cell subsets by Flt3 ligand
Authors: Maraskovsky Eugene , Daro Elizabeth , Roux Eileen , Teepe Mark , Maliszewski Charlie R. , Hoek Jeannie , Caron Dania , Lebsack Mel E. , McKenna Hilary J.
Published: October 2019

Dendritic cells (DCs) represent a family of ontogenically distinct leukocytes involved in immune response regulation. The ability of DCs to stimulate T-cell immunity has led to their use as vectors for immunotherapy vaccines. However, it is unclear whether and to what degree in vitro–generated DCs are representative of DCs that develop in vivo. Treatment of mice with human Flt3 ligand (FL) dramatically increases the number of DCs. We report here that administration of FL to healthy human volunteers increased the number of circulating CD11c+ IL-3Rlow DC (mean 44-fold) and CD11c− IL-3Rhigh DC precursors (mean 12-fold). Moreover, the CD11c+ DCs were efficient stimulators of T cells in vitro. Thus, FL can expand the number of circulating, functionally competent human DCs in vivo.
Expression of connexin 43 (Cx43) is critical for normal hematopoiesis
Authors: Montecino-Rodriguez Encarnacion , Leathers Hyosuk , Dorshkind Kenneth
Published: October 2019

Gap junctions are intercellular channels, formed by individual structural units known as connexins (Cx), that allow the intercellular exchange of various messenger molecules. The finding that numbers of Cx43-type gap junctions in bone marrow are elevated during establishment and regeneration of the hematopoietic system has led to the hypothesis that expression of Cx43 is critical during the initiation of blood cell formation. To test this hypothesis, lymphoid and myeloid development were examined in mice with a targeted disruption of the gene encoding Cx43. Because Cx43−/− mice die perinatally, initial analyses were performed on Cx43−/−, Cx43+/−, and Cx43+/+ embryos and newborns. The data indicate that lack of Cx43 expression during embryogenesis compromises the terminal stages of primary T and B lymphopoiesis. Cx43−/− embryos and neonates had a reduced frequency of CD4+ and T-cell receptor-expressing thymocytes and surface IgM+cells compared to their Cx43+/+ littermates. Surprisingly, Cx43+/− embryos/neonates also showed defects in B- and T-cell development similar to those observed in Cx43−/− littermates, but their hematopoietic system was normal at 4 weeks of age. However, the regeneration of lymphoid and myeloid cells was severely impaired in the Cx43+/− mice after cytoablative treatment. Taken together, these data indicate that loss of a single Cx43 allele can affect blood cell formation. Finally, the results of reciprocal bone marrow transplants between Cx43+/+ and Cx43+/− mice and examination of hematopoietic progenitors and stromal cells in vitro indicates that the primary effects of Cx43 are mediated through its expression in the hematopoietic microenvironment.
JNK and p38 are activated by erythropoietin (EPO) but are not induced in apoptosis following EPO withdrawal in EPO-dependent HCD57 cells
Authors: Jacobs-Helber Sarah M. , Ryan John J. , Sawyer Stephen T.
Published: October 2019

Jun N-terminal kinase (JNK) and p38, members of the mitogen-activated protein kinase family of serine/threonine kinases, are activated as a result of cellular stress but may also play a role in growth factor-induced proliferation and/or survival or differentiation of many cells. A recent report has implicated JNK and p38 in the induction of apoptosis in the erythropoietin (EPO)-dependent erythroid cell line HCD57 following EPO withdrawal, whereas our previously reported data did not support a role for JNK in growth factor withdrawal-induced apoptosis in HCD57 cells. Therefore, further testing was done to see if JNK was activated in EPO withdrawal-induced apoptosis; the study was extended to p38 and characterized the effect of EPO on JNK and p38 activities. Treatment of HCD57 cells with EPO resulted in a gradual and sustained activation of both JNK and p38 activity; these activities decreased on EPO withdrawal. Transient activation of p42/p44 extracellular signal-related kinases (ERK) was also detected. Inhibition of ERK activity inhibited proliferation in EPO-treated cells but neither induced apoptosis nor activated JNK. Inhibition of p38 activity inhibited proliferation but did not protect HCD57 cells from apoptosis induced by EPO withdrawal. Treatment of HCD57 cells with tumor necrosis factor-alpha induced JNK activation but did not induce apoptosis. These results implicate JNK, p38, and ERK in EPO-induced proliferation and/or survival of erythroid cells but do not support a role for JNK or p38 in apoptosis induced by EPO withdrawal from erythroid cells.
Hemophilic factor VIII C1- and C2-domain missense mutations and their modeling to the 1.5-angstrom human C2-domain crystal structure
Authors: Liu Miao-Liang , Shen Betty W. , Nakaya Shelley , Pratt Kathleen P. , Fujikawa Kazuo , Davie Earl W. , Stoddard Barry L. , Thompson Arthur R.
Published: October 2019

Factor VIII C domains contain key binding sites for von Willebrand factor (vWF) and phospholipid membranes. Hemophilic patients were screened for factor VIII C-domain mutations to provide a well-characterized series. Mutated residues were localized to the high-resolution C2 structure and to a homology model of C1. Of 30 families found with mutations in the C domains, there were 14 missense changes, and 9 of these were novel. Of the missense mutations, 10 were associated with reduced vWF binding and 8 were at residues with surface-exposed side chains. Six of the 10 mutants had nearly equivalent factor VIII clotting activity and antigen level, suggesting that reduced vWF binding could cause hemophilia by reducing factor VIII stability in circulation. When the present series was combined with previously described mutations from an online international database, 11 C1 and C2 mutations in patients with mild or moderately severe hemophilia A were associated with antibody-inhibitor development in at least one affected individual. Of these substitutions, 6 occurred at surface-exposed residues. As further details of the C1 structure and its interface with C2 become available, and as binding studies are performed on the plasma of more patients with hemophilic C-domain mutations, prediction of surface binding sites should improve, allowing confirmation by site-specific mutagenesis of surface-exposed residues.
Recombinant staphylokinase variants with reduced antigenicity due to elimination of B-lymphocyte epitopes
Authors: Laroche Yves , Heymans Stephane , Capaert Sophie , De Cock Frans , Demarsin Eddy , Collen Désiré
Published: October 2019

Site directed mutagenesis (350 variants) of recombinant staphylokinase (SakSTAR), a potent fibrin-selective thrombolytic agent, was undertaken in order to reduce its antigenicity while maintaining its potency. Variants with K35A, (ie, Lys[K] in position 35 substituted with Ala[A]), E65D or E65Q, K74R or K74Q, E80A+D82A, K130T, and K135R displayed increased enzymatic activity or reduced binding of human staphylokinase-specific antibodies. Additive mutagenesis identified 8 variants with intact thrombolytic potencies, which absorbed down to less than a third of SakSTAR-specific antibodies. Intra-arterial administration in 61 patients with peripheral arterial occlusion caused no significant allergic reactions. Median neutralizing antibody titers (with 15 to 85 percentiles), expressed as microgram (μg) compound neutralized per milliliter plasma, were 4.4 (0.3 to 49) for the variants, compared with 12 (4 to 100) in 70 patients given wild-type SakSTAR (P = .002 by Mann-Whitney rank sum test). Overt neutralizing antibody induction (more than 5 μg compound neutralized per milliliter plasma) was observed in 57 of 70 patients (81%) given wild-type SakSTAR, but only in 28 of 60 patients (47%) treated with variants (P < .0001 by Fisher exact test). On the basis of this study, the variant SakSTAR (K35A, E65Q, K74R, D82A, S84A, T90A, E99D, T101S, E108A, K109A, K130T, K135R) (code SY155) has been selected for further clinical development.
Impact of the patient population on the risk for heparin-induced thrombocytopenia
Authors: Warkentin Theodore E. , Sheppard Jo-Ann I. , Horsewood Peter , Simpson Patricia J. , Moore Jane C. , Kelton John G.
Published: October 2019

The frequency of immune heparin-induced thrombocytopenia (HIT) varies among prospective studies. It is unknown whether this is caused by differences in the heparin preparations, the patient populations, or the types of serologic assay used to confirm the diagnosis. Seven hundred forty-four patients were studied from 3 different clinical treatment settings, as follows: unfractionated heparin (UFH) during or after cardiac surgery (n = 100), UFH after orthopedic surgery (n = 205), and low-molecular-weight heparin (LMWH) after orthopedic surgery (n = 439). Both an activation assay and an antigen assay were used to detect heparin-dependent IgG (HIT-IgG) antibodies. By activation assay, the frequency of HIT-IgG formation ranged from a low of 3.2% in orthopedic patients receiving LMWH to a high of 20% in cardiac patients receiving UFH; by antigen assay, the corresponding frequencies ranged from 7.5% to 50%. Both UFH use (P = .002) and cardiac surgery (P = .01) were more likely to be associated with HIT-IgG formation. However, among patients in whom HIT-IgG formed and who were administered UFH, the probability for HIT was higher among orthopedic patients than among cardiac patients (by activation assay: 52.6% compared with 5%; odds ratio, 21.1 [95% CI, 2.2-962.8]; P = .001; by antigen assay: 34.5% compared with 2.0%; odds ratio, 25.8 [95% CI, 3.2-1141]; P < .001). It is concluded that there is an unexpected dissociation between the frequency of HIT-IgG formation and the risk for HIT that is dependent on the patient population. HIT-IgG antibodies are more likely to form in patients who undergo cardiac surgery than in orthopedic patients, but among patients in whom antibodies do form, orthopedic patients are more likely to develop HIT.
Vertical transmission of HCV is related to maternal peripheral blood mononuclear cell infection
Authors: Azzari Chiara , Resti Massimo , Moriondo Maria , Ferrari Roberto , Lionetti Paolo , Vierucci Alberto
Published: October 2019

Infection of peripheral blood mononuclear cells (PBMNCs) has been demonstrated to be a crucial event in the vertical transmission of viruses, and it is known that hepatitis C virus (HCV) can infect PBMNCs. The relationship between vertical transmission of HCV and the presence of positive and negative strands of HCV-RNA in the PBMNCs of HCV-carrier mothers was investigated using reverse transcriptase–polymerase chain reaction (RT-PCR). During the study, 13 consecutive mothers who transmitted infection to their offspring and 53 consecutive mothers who did not were examined. The positive strand of HCV-RNA was identified in the PBMNCs of all mothers who transmitted the infection and in 13 of 53 mothers who did not (P < 10−6). The HCV-RNA−strand was found in 5 of 13 mothers who transmitted the infection, and the strand was not found in the mothers who did not transmit the infection (P = .0001). Neither maternal PBMNC infection nor HCV transmission to the offspring was significantly related to the viral genotype or to the maternal viral load. These data show that maternal PBMNC infection by HCV and viral replicative activity in PBMNCs are important factors in the transmission of HCV from mother to child. The mechanism through which HCV infection of PBMNC favors vertical transmission of the virus is still incompletely understood.
Identification of critical antigen-specific mechanisms in the development of immune thrombocytopenic purpura in mice
Authors: Nieswandt Bernhard , Bergmeier Wolfgang , Rackebrandt Kirsten , Gessner J. Engelbert , Zirngibl Hubert
Published: October 2019

The pathogenic effects of antiplatelet antibodies were investigated in mice. Monoclonal antibodies (mAbs) of different immunoglobulin G subclass directed against mouse GPIIbIIIa, GPIIIa, GPIbα, GPIb-IX, GPV, and CD31 were generated and characterized biochemically. MAbs against GPIb-IX, GPV, CD31, and linear epitopes on GPIIIa had mild and transient effects on platelet counts and induced no spontaneous bleeding. Anti-GPIbα mAbs induced profound irreversible thrombocytopenia (< 3% of normal) by Fc-independent mechanisms but only had minor effects on hematocrits. In contrast, injection of intact mAbs, but not F(ab)2 fragments, against conformational epitopes on GPIIbIIIa, induced irreversible thrombocytopenia, acute systemic reactions, hypothermia, decreased hematocrits, and a paradoxical loss of surface GPIIbIIIa on platelets in vivo, the latter suggesting the formation of platelet-derived microparticles. Blockage of platelet-activating factor receptors inhibited the acute reactions, but not thrombocytopenia, loss of GPIIbIIIa, and decreases in hematocrits. Repeated injections of low doses of anti-GPIIbIIIa antibodies resulted in profound thrombocytopenia and bleeding, whereas no acute systemic reactions were observed. These data strongly suggest that the identity of the target antigen recognized by antiplatelet antibodies determines the mechanisms of platelet destruction and the severity of bleeding in mice, the latter depending on previously unrecognized anti-GPIIbIIIa-specific inflammatory mechanisms.
Abnormal T-cell repertoire is consistent with immune process underlying the pathogenesis of paroxysmal nocturnal hemoglobinuria
Authors: Karadimitris Anastasios , Manavalan John S. , Thaler Howard T. , Notaro Rosario , Araten David J. , Nafa Khedoudja , Roberts Irene A.G. , Weksler Marc E. , Luzzatto Lucio
Published: October 2019

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder of the hematopoietic stem cell (HSC). Somatic mutations in thePIG-A gene result in the deficiency of several glycosylphosphatidylinositol-linked proteins from the surface of blood cells. This explains intravascular hemolysis but does not explain the mechanism of bone marrow failure that is almost invariably seen in PNH. In view of the close relationship between PNH and idiopathic aplastic anemia (IAA), it has been suggested that the 2 disorders might have a similar cellular pathogenesis, namely, that autoreactive T-cell clones are targeting HSCs. In this paper, we searched for abnormally expanded T-cell clones by size analysis of the complementarity-determining region 3 (CDR3) in the beta variable chain (BV) messenger RNA (mRNA) of the T-cell receptor (TCR) in 19 patients with PNH, in 7 multitransfused patients with hemoglobinopathy. and in 11 age-matched healthy individuals. We found a significantly higher degree of skewness in the TCR BV repertoire of patients with PNH, compared with controls (R2 values 0.82 vs 0.91,P < .001). The mean frequency of skewed families per individual was increased by more than 2-fold in patients with PNH, compared with controls (28% ± 19.6% vs 11.4% ± 6%,P = .002). In addition, several TCR BV families were significantly more frequently skewed in patients with PNH than in controls. These findings provide experimental support for the concept that PNH, like IAA, has an immune pathogenesis. In addition, the identification of expanded T-cell clones by CDR3 size analysis will help to investigate the effect of HSC-specific T cells on normal and PNH HSCs.
Ex vivo expanded peripheral blood progenitor cells provide rapid neutrophil recovery after high-dose chemotherapy in patients with breast cancer
Authors: McNiece Ian , Jones Roy , Bearman Scott I. , Cagnoni Pablo , Nieto Yago , Franklin Wilbur , Ryder John , Steele Andrea , Stoltz Judy , Russell Peggy , McDermitt Janet , Hogan Christopher , Murphy James , Shpall Elizabeth J.
Published: October 2019

Ex vivo expanded peripheral blood progenitor cells (PBPCs) have been proposed as a source of hematopoietic support to decrease or eliminate the period of neutropenia after high-dose chemotherapy. CD34 cells were selected from rhG-CSF mobilized PBPCs from patients with breast cancer and were cultured for 10 days in defined media containing 100 ng/mL each of rhSCF, rhG-CSF, and PEG-rhMGDF in 1 L Teflon bags at 20 000 cells/mL. After culture the cells were washed and reinfused on day 0 of transplantation. On day +1, cohort 1 patients (n = 10) also received an unexpanded CD34-selected PBPC product. These patients engrafted neutrophils (absolute neutrophil count, >500/μL) in a median of 6 (range, 5-14) days. Cohort 2 patients (n = 11), who received expanded PBPCs only, engrafted neutrophils in a median of 8 (range, 4-16) days. In comparison, the median time to neutrophil engraftment in a historical control group of patients (n = 100) was 9 days (range, 7-30 days). All surviving patients are now past the 15-month posttransplantation stage with no evidence of late graft failure. The total number of nucleated cells harvested after expansion culture was shown to be the best predictor of time to neutrophil engraftment, with all patients receiving more than 4 × 107 cells/kg, engrafting neutrophils by day 8. No significant effect on platelet recovery was observed in any patient. These data demonstrate that PBPCs expanded under the conditions defined can shorten the time to engraftment of neutrophils compared with historical controls and that the rate of engraftment is related to the dose of expanded cells transplanted.
Study on cyanidin metabolism in petals of pink-flowered strawberry based on transcriptome sequencing and metabolite analysis
Authors: Xue Li , Wang Jian , Zhao Jun , Zheng Yang , Wang Hai-Feng , Wu Xue , Xian Cheng , Lei Jia-Jun , Zhong Chuan-Fei , Zhang Yun-Tao
Published: October 2019

Background

Pink-flowered strawberry is a promising new ornamental flower derived from intergeneric hybridization (Fragaria × Potentilla) with bright color, a prolonged flowering period and edible fruits. Its flower color ranges from light pink to red. Pigment compounds accumulated in its fruits were the same as in cultivated strawberry fruits, but different from that in its flowers. However, the transcriptional events underlying the anthocyanin biosynthetic pathway have not been fully characterized in petal coloration. To gain insights into the regulatory networks related to anthocyanin biosynthesis and identify the key genes, we performed an integrated analysis of the transcriptome and metabolome in petals of pink-flowered strawberry.

Results

The main pigments of red and dark pink petals were anthocyanins, among which cyanidins were the main compound. There were no anthocyanins detected in the white-flowered hybrids. A total of 50,285 non-redundant unigenes were obtained from the transcriptome databases involved in red petals of pink-flowered strawberry cultivar Sijihong at three development stages. Amongst the unigenes found to show significant differential expression, 57 were associated with anthocyanin or other flavonoid biosynthesis, in which they were regulated by 241 differentially expressed members of transcription factor families, such as 40 MYBs, 47 bHLHs, and 41 NACs. Based on a comprehensive analysis relating pigment compounds to gene expression profiles, the mechanism of flower coloration was examined in pink-flowered strawberry. A new hypothesis was proposed to explain the lack of color phenotype of the white-flowered strawberry hybrids based on the transcriptome analysis. The expression patterns of FpDFR and FpANS genes corresponded to the accumulation patterns of cyanidin contents in pink-flowered strawberry hybrids with different shades of pink. Moreover, FpANS, FpBZ1 and FpUGT75C1 genes were the major factors that led to the absence of anthocyanins in the white petals of pink-flowered strawberry hybrids. Meanwhile, the competitive effect of FpFLS and FpDFR genes might further inhibit anthocyanin synthesis.

Conclusions

The data presented herein are important for understanding the molecular mechanisms underlying the petal pigmentation and will be powerful for integrating novel potential target genes to breed valuable pink-flowered strawberry cultivars.
Effects of eccentric exercise in patients with subacromial impingement syndrome: a systematic review and meta-analysis
Authors: Larsson Robin , Bernhardsson Susanne , Nordeman Lena
Published: October 2019

Background

Subacromial impingement syndrome is a common problem in primary healthcare. It often include tendinopathy. While exercise therapy is effective for this condition, it is not clear which type of exercise is the most effective. Eccentric exercises has proven effective for treating similar tendinopathies in the lower extremities. The aim of this systematic review was therefore to investigate the effects of eccentric exercise on pain and function in patients with subacromial impingement syndrome compared with other exercise regimens or interventions. A secondary aim was to describe the included components of the various eccentric exercise regimens that have been studied.

Methods

Systematic searches of PubMed, Cochrane Library and PEDro by two independent authors. Included studies were assessed using the PEDro scale for quality and the Cochrane scale for clinical relevance by two independent authors. Data were combined in meta-analyses. GRADE was applied to assess the certainty of evidence.

Results

Sixty-eight records were identified. Seven studies (eight articles) were included, six were meta-analysed (n = 281). Included studies were of moderate quality (median PEDro score 7, range 5–8). Post-treatment pain was significantly lower after eccentric exercise compared with other exercise: MD -12.3 (95% CI − 17.8 to − 6.8, I2 = 7%,p < 0.001), but this difference was not clinically important. Eccentric exercise provided no significant post-treatment improvement in function compared with other exercise: SMD -0.10 (95% CI − 0.79 to 0.58, I2 = 85%,p = 0.76). Painful eccentric exercise showed no significant difference compared to pain-free eccentric exercise. Eccentric training regimes showed both similarities and diversity. Intervention duration of 6–8 weeks was almost as effective as 12 weeks.

Conclusions

Evidence of low certainty suggests that eccentric exercise may provide a small but likely not clinically important reduction in pain compared with other types of exercise in patients with subacromial impingement syndrome. It is uncertain whether eccentric exercise improves function more than other types of exercise (very low certainty of evidence). Methodological limitations of existing studies make these findings susceptible to change in the future.

Trial registration

PROSPEROCRD42019126917, date of registration: 29-03-2019.
Down-regulated of SREBP-1 in circulating leukocyte is a risk factor for atherosclerosis: a case control study
Authors: Peng Chunyan , Lei Pan , Li Xiandong , Xie Huaqiang , Yang Xiaowen , Zhang Tao , Cao Zheng , Zhang Jicai
Published: October 2019

Background

Sterol regulatory-element binding proteins (SREBPs) and mir-33 (miR-33a, miR-33b), which are encoded by the introns of SREBPs, are key factors in the lipid metabolism pathway. SREBPs mRNA in circulating leucocyte and carotid plaques, along with various risk factors that associated with Coronary Atherosclerotic Disease (CAD) were investigated in a central Chinese cohort.

Methods

A total of 218 coronary atherosclerotic disease (CAD) patients, and 178 non-CAD controls, were recruited to collect leukocytes. Carotid plaques and peripheral blood were obtained from CAD patients undergoing carotid endarterectomy (CEA) (n = 12) while THP-1 and peripheral blood mononuclear cells (PBMCs) were stimulated with Oxidized low-density lipoprotein (ox-LDL) to establish an in vitro foam cell formation model. SREBPs and miR-33 levels were quantified by qPCR. Routine biochemical markers were measured using standard procedures.

Results

SREBP-1 mRNA level of circulating leucocytes in CAD patients were significantly lower than in non-CAD controls (p = 0.005). After stratification coronary artery atherosclerotic complexity, we detected a significant reduction of SREBP-1 in high-risk complexity CAD patients (SYNTAX score > 23) (p = 0.001). Logistic regression analysis indicated that decreased expression of SREBP-1 was a risk factor of CAD (odds ratio (OR) =0.48, 95% confidence interval (CI) = 0.30~0.76, p = 0.002) after adjusting clinical confounders; the mRNA levels of SREBPs in carotid plaques correlated with the corresponding value in circulating leukocytes (SREBP-1 r = 0.717, p = 0.010; SREBP-2 r = 0.612, p = 0.034). Finally, there was no significant difference in serum miR-33 levels between CAD patients and controls.

Conclusions

Our finding suggesting a potential role in the adjustment of established CAD risk. The future clarification of how SREBP-1 influence the pathogenesis of CAD might pave the way for the development of novel therapeutic methods.
Transcriptional activation of CBFβ by CDK11p110 is necessary to promote osteosarcoma cell proliferation
Authors: Feng Yong , Liao Yunfei , Zhang Jianming , Shen Jacson , Shao Zengwu , Hornicek Francis , Duan Zhenfeng
Published: October 2019

Background

Aberrant expression of cyclin-dependent protein kinases (CDK) is a hallmark of cancer. CDK11 plays a crucial role in cancer cell growth and proliferation. However, the molecular mechanisms of CDK11 and CDK11 transcriptionally regulated genes are largely unknown.

Methods

In this study, we performed a global transcriptional analysis using gene array technology to investigate the transcriptional role of CDK11 in osteosarcoma. The promoter luciferase assay, chromatin immunoprecipitation assay, and Gel Shift assay were used to identify direct transcriptional targets of CDK11. Clinical relevance and function of core-binding factor subunit beta (CBFβ) were further accessed in osteosarcoma.

Results

We identified a transcriptional role of protein-DNA interaction for CDK11p110, but not CDK11p58, in the regulation of CBFβ expression in osteosarcoma cells. The CBFβ promoter luciferase assay, chromatin immunoprecipitation assay, and Gel Shift assay confirmed that CBFβ is a direct transcriptional target of CDK11. High expression of CBFβ is associated with poor outcome in osteosarcoma patients. Expression of CBFβ contributes to the proliferation and metastatic behavior of osteosarcoma cells.

Conclusions

These data establish CBFβ as a mediator of CDK11p110dependent oncogenesis and suggest that targeting the CDK11- CBFβ pathway may be a promising therapeutic strategy for osteosarcoma treatment.

Graphical Abstract
Sox2 promotes expression of the ST6Gal-I glycosyltransferase in ovarian cancer cells
Authors: Dorsett Kaitlyn A. , Jones Robert B. , Ankenbauer Katherine E. , Hjelmeland Anita B. , Bellis Susan L.
Published: October 2019

Background

The ST6Gal-I glycosyltransferase, which adds α2–6-linked sialic acids toN-glycosylated proteins is upregulated in a wide range of malignancies including ovarian cancer. Prior studies have shown that ST6Gal-I-mediated sialylation of select surface receptors remodels intracellular signaling to impart cancer stem cell (CSC) characteristics. However, the mechanisms that contribute to ST6Gal-I expression in stem-like cancer cells are poorly understood.

Results

Herein, we identify the master stem cell transcription factor, Sox2, as a novel regulator of ST6Gal-I expression. Interestingly,SOX2andST6GAL1are located within the same tumor-associated amplicon, 3q26, and these two genes exhibit coordinate gains in copy number across multiple cancers including ~ 25% of ovarian serious adenocarcinomas. In conjunction with genetic co-amplification, our studies suggest that Sox2 directly binds theST6GAL1promoter to drive transcription. ST6Gal-I expression is directed by at least four distinct promoters, and we identified the P3 promoter as the predominant promoter utilized by ovarian cancer cells. Chromatin Immunoprecipitation (ChIP) assays revealed that Sox2 binds regions proximal to the P3 promoter. To confirm that Sox2 regulates ST6Gal-I expression, Sox2 was either overexpressed or knocked-down in various ovarian cancer cell lines. Sox2 overexpression induced an increase in ST6Gal-I mRNA and protein, as well as surface α2–6 sialylation, whereas Sox2 knock-down suppressed levels of ST6Gal-I mRNA, protein and surface α2–6 sialylation.

Conclusions

These data suggest a process wherebySOX2andST6GAL1are coordinately amplified in cancer cells, with the Sox2 protein then binding theST6GAL1promoter to further augment ST6Gal-I expression. Our collective results provide new insight into mechanisms that upregulate ST6Gal-I expression in ovarian cancer cells, and also point to the possibility that some of the CSC characteristics commonly attributed to Sox2 may, in part, be mediated through the sialyltransferase activity of ST6Gal-I.
Survival by colon cancer stage and screening interval in Lynch syndrome: a prospective Lynch syndrome database report
Authors: Dominguez-Valentin Mev , Seppälä Toni T. , Sampson Julian R. , Macrae Finlay , Winship Ingrid , Evans D. Gareth , Scott Rodney J. , Burn John , Möslein Gabriela , Bernstein Inge , Pylvänäinen Kirsi , Renkonen-Sinisalo Laura , Lepistö Anna , Lindblom Annika , Plazzer John-Paul , Tjandra Douglas , Thomas Huw , Green Kate , Lalloo Fiona , Crosbie Emma J. , Hill James , Capella Gabriel , Pineda Marta , Navarro Matilde , Vidal Joan Brunet , Rønlund Karina , Nielsen Randi Thyregaard , Yilmaz Mette , Elvang Louise Laurberg , Katz Lior , Nielsen Maartje , ten Broeke Sanne W. , Nakken Sigve , Hovig Eivind , Sunde Lone , Kloor Matthias , Knebel Doeberitz Magnus v , Ahadova Aysel , Lindor Noralane , Steinke-Lange Verena , Holinski-Feder Elke , Mecklin Jukka-Pekka , Møller Pål
Published: October 2019

Background

We previously reported that in pathogenic mismatch repair (path_MMR) variant carriers, the incidence of colorectal cancer (CRC) was not reduced when colonoscopy was undertaken more frequently than once every 3 years, and that CRC stage and interval since last colonoscopy were not correlated.

Methods

The Prospective Lynch Syndrome Database (PLSD) that records outcomes of surveillance was examined to determine survival after colon cancer in relation to the time since previous colonoscopy and pathological stage. Only path_MMR variants scored by the InSiGHT variant database as class 4 or 5 (clinically actionable) were included in the analysis.

Results

Ninety-nine path_MMR carriers had no cancer prior to or at first colonoscopy, but subsequently developed colon cancer. Among these, 96 were 65 years of age or younger at diagnosis, and included 77 path_MLH1, 17 path_MSH2, and 2 path_MSH6 carriers. The number of cancers detected within < 1.5, 1.5–2.5, 2.5–3.5 and at > 3.5 years after previous colonoscopy were 9, 43, 31 and 13, respectively. Of these, 2, 8, 4 and 3 were stage III, respectively, and only one stage IV (interval 2.5–3.5 years) disease. Ten-year crude survival after colon cancer were 93, 94 and 82% for stage I, II and III disease, respectively (p < 0.001). Ten-year crude survival when the last colonoscopy had been < 1.5, 1.5–2.5, 2.5–3.5 or > 3.5 years before diagnosis, was 89, 90, 90 and 92%, respectively (p = 0.91).

Conclusions

In path_MLH1 and path_MSH2 carriers, more advanced colon cancer stage was associated with poorer survival, whereas time since previous colonoscopy was not. Although the numbers are limited, together with our previously reported findings, these results may be in conflict with the view that follow-up of path_MMR variant carriers with colonoscopy intervals of less than 3 years provides significant benefit.
Birth, expansion, and death of VCY-containing palindromes on the human Y chromosome
Authors: Shi Wentao , Massaia Andrea , Louzada Sandra , Handsaker Juliet , Chow William , McCarthy Shane , Collins Joanna , Hallast Pille , Howe Kerstin , Church Deanna M. , Yang Fengtang , Xue Yali , Tyler-Smith Chris
Published: October 2019

Background

Large palindromes (inverted repeats) make up substantial proportions of mammalian sex chromosomes, often contain genes, and have high rates of structural variation arising via ectopic recombination. As a result, they underlie many genomic disorders. Maintenance of the palindromic structure by gene conversion between the arms has been documented, but over longer time periods, palindromes are remarkably labile. Mechanisms of origin and loss of palindromes have, however, received little attention.

Results

Here, we use fiber-FISH, 10x Genomics Linked-Read sequencing, and breakpoint PCR sequencing to characterize the structural variation of the P8 palindrome on the human Y chromosome, which contains two copies of the VCY (Variable Charge Y) gene. We find a deletion of almost an entire arm of the palindrome, leading to death of the palindrome, a size increase by recruitment of adjacent sequence, and other complex changes including the formation of an entire new palindrome nearby. Together, these changes are found in ~ 1% of men, and we can assign likely molecular mechanisms to these mutational events. As a result, healthy men can have 1–4 copies of VCY.

Conclusions

Gross changes, especially duplications, in palindrome structure can be relatively frequent and facilitate the evolution of sex chromosomes in humans, and potentially also in other mammalian species.
Global impact of somatic structural variation on the DNA methylome of human cancers
Authors: Zhang Yiqun , Yang Lixing , Kucherlapati Melanie , Hadjipanayis Angela , Pantazi Angeliki , Bristow Christopher A. , Lee Eunjung Alice , Mahadeshwar Harshad S. , Tang Jiabin , Zhang Jianhua , Seth Sahil , Lee Semin , Ren Xiaojia , Song Xingzhi , Sun Huandong , Seidman Jonathan , Luquette Lovelace J. , Xi Ruibin , Chin Lynda , Protopopov Alexei , Park Peter J. , Kucherlapati Raju , Creighton Chad J.
Published: October 2019

Background

Genomic rearrangements exert a heavy influence on the molecular landscape of cancer. New analytical approaches integrating somatic structural variants (SSVs) with altered gene features represent a framework by which we can assign global significance to a core set of genes, analogous to established methods that identify genes non-randomly targeted by somatic mutation or copy number alteration. While recent studies have defined broad patterns of association involving gene transcription and nearby SSV breakpoints, global alterations in DNA methylation in the context of SSVs remain largely unexplored.

Results

By data integration of whole genome sequencing, RNA sequencing, and DNA methylation arrays from more than 1400 human cancers, we identify hundreds of genes and associated CpG islands (CGIs) for which the nearby presence of a somatic structural variant (SSV) breakpoint is recurrently associated with altered expression or DNA methylation, respectively, independently of copy number alterations. CGIs with SSV-associated increased methylation are predominantly promoter-associated, while CGIs with SSV-associated decreased methylation are enriched for gene body CGIs. Rearrangement of genomic regions normally having higher or lower methylation is often involved in SSV-associated CGI methylation alterations. Across cancers, the overall structural variation burden is associated with a global decrease in methylation, increased expression in methyltransferase genes and DNA damage response genes, and decreased immune cell infiltration.

Conclusion

Genomic rearrangement appears to have a major role in shaping the cancer DNA methylome, to be considered alongside commonly accepted mechanisms including histone modifications and disruption of DNA methyltransferases.
French national survey of dog and cat owners on the deworming behaviour and lifestyle of pets associated with the risk of endoparasites
Authors: Roussel Clarisse , Drake Jason , Ariza Juan Manuel
Published: October 2019

Background

Endoparasites in dogs and cats are a concern related to pet health and zoonotic risks. Several determinants may affect the endoparasite transmission and infection of dogs and cats such as pet’s lifestyle or regional parasite distribution. Although different zoonotic endoparasites, such as Toxocara spp. and Echinococcus spp., have been identified in France, little information exists about the deworming behaviors of owners or the frequency of occurrence of risk factors associated with endoparasite infection or transmission. Deworming guidelines, such as those created by the European Scientific Counsel Companion Animal Parasites (ESCCAP), recommend a deworming frequency according to the risk of infection of every pet and the potential risk for zoonotic transmission. The objectives of this study were to explore how lifestyles of dogs and cats from France were related to a particular risk of endoparasites and assess whether deworming frequencies complied with ESCCAP recommendations.

Methods

French data were extracted from a database created during a recent European pet owner survey regarding endoparasitic infection risk. Dogs and cats were grouped into risk categories based upon the ESCCAP guidelines. The compliance between the actual and recommended deworming frequencies were explored among the regions surveyed.

Results

The majority of dogs and cats were older than 6 months, had outdoor access, had contact with children or elderly people, and lived in rural and town areas. Most of the dogs were in contact with other dogs, snails or prey (83%), and ate slugs, snails, grass or dug in the garden (68%). Likewise, most of the cats hunted outside (57%) and caught prey animals (52%). Consequently, most of the dogs (89%) and cats (53%) were considered to be in the highest-risk category (D). However, independent of the region, the average deworming compliance for dogs was poor (6%). While deworming compliance for cats in category A (low-risk) was excellent (94%), for cats in category D it was poor (6%).

Conclusions

Deworming compliance is needed to enhance pet health and reduce zoonotic risks. Future studies are warranted to thoroughly investigate the compliance and effectiveness of deworming protocols, and the risk factors associated with endoparasites in France.
A field-based modeling study on ecological characterization of hourly host-seeking behavior and its associated climatic variables in Aedes albopictus
Authors: Yin Qingqing , Li Li , Guo Xiang , Wu Rangke , Shi Benyun , Wang Yuji , Liu Yingjie , Wu Shang , Pan Yicheng , Wang Qi , Xie Tian , Hu Tian , Xia Dan , Xia Shang , Kambalame Dzinkambani Moffat , Li Wanyu , Song Zhangyao , Zhou Siyun , Deng Ye , Xie Yu , Zhou Xiao-Nong , Wang Chunmei , Chen Xiao-Guang , Zhou Xiaohong
Published: October 2019

Background

The global spread of mosquito-borne diseases (MBD) has presented increasing challenges to public health. The transmission of MBD is mainly attributable to the biting behaviors of female mosquitoes. However, the ecological pattern of hourly host-seeking behavior in Aedes albopictus and its association with climatic variables are still not well understood, especially for a precise requirement for establishing an effective risk prediction system of MBD transmission.

Methods

Mosquito samples and data on mosquito hourly density and site-specific climatic variables, including temperature, relative humidity, illuminance and wind speed, were collected simultaneously in urban outdoor environments in Guangzhou during 2016–2018. Kernel regression models were used to assess the temporal patterns of hourly host-seeking behavior in mosquito populations, and negative binomial regression models in the Bayesian framework were used to investigate the associations of host-seeking behavior with climatic variables.

Results

Aedes albopictus was abundant, constituting 82% (5569/6790) of the total collected mosquitoes. Host-seeking behavior in Ae. albopictus varied across time and was significantly influenced by climatic variables. The predicted hourly mosquito densities showed non-linear relationships with temperature and illuminance, whereas density increased with relative humidity but generally decreased with wind speed. The range of temperature estimates for female biting was 16.4–37.1 °C, peaking at 26.5 °C (95% credible interval: 25.3–28.1). During the favorable periods, biting behavior of female Ae. albopictus was estimated to occur frequently all day long, presenting a bimodal distribution with peaks within 2–3 h around both dawn and dusk (05:00–08:00 h and 16:00–19:00 h). Moreover, a short-term association in hourly density between the females and males was found.

Conclusions

Our field-based modeling study reveals that hourly host-seeking behavior of Ae. albopictus exhibits a complex pattern, with hourly variation constrained significantly by climatic variables. These findings lay a foundation for improving MBD risk assessments as well as practical strategies for vector control. For instances of all-day-long frequent female biting during the favorable periods in Guangzhou, effective integrated mosquito control measures must be taken throughout the day and night.
First complete genome sequence and comparative analysis of Salmonella enterica subsp. diarizonae serovar 61:k:1,5,(7) indicates host adaptation traits to sheep
Authors: Uelze Laura , Borowiak Maria , Deneke Carlus , Jacobs Cécile , Szabó István , Tausch Simon H. , Malorny Burkhard
Published: October 2019

Background

The Salmonella enterica subsp. diarizonae serovar 61:k:1,5,(7) (SASd) has been found to be host-adapted to sheep, with a high prevalence in sheep herds worldwide. Infections are usually sub-clinical, however the serovar has the potential to cause diarrhea, abortions and chronic proliferative rhinitis. Although occurrence and significance of SASd infections in sheep have been extensively studied, the genetic mechanism underlying this unusual host-adaptation have remained unknown, due to a lack of (a) available high-quality genome sequence(s).

Results

We utilized Nanopore and Illumina sequencing technologies to generate a de novo assembly of the 4.88-Mbp complete genome sequence of the SASd strain 16-SA00356, isolated from the organs of a deceased sheep in 2016. We annotated and analyzed the genome sequence with the aim to gain a deeper understanding of the genome characteristics associated with its pathogenicity and host adaptation to sheep. Overall, we found a number of interesting genomic features such as several prophage regions, a VirB4/D4 plasmid and novel genomic islands. By comparing the genome of 16-SA00356 to other S. enterica serovars we found that SASd features an increased number of pseudogenes as well as a high level of genomic rearrangements, both known indicators of host-adaptation.

Conclusions

With this sequence, we provide the first complete and closed genome sequence of a SASd strain. With this study, we provide an important basis for an understanding of the genetic mechanism that underlie pathogenicity and host adaptation of SASd to sheep.