bluuebunny/crossref_metadata_2025_split huggingface dataset:
The human antimicrobial and chemotactic peptides LL-37 and α-defensins are expressed by specific lymphocyte and monocyte populations
Authors: Agerberth Birgitta , Charo Jehad , Werr Joachim , Olsson Berit , Idali Farah , Lindbom Lennart , Kiessling Rolf , Jörnvall Hans , Wigzell Hans , Gudmundsson Gudmundur H. 
Published: October 2019

AbstractWe identified antibacterial components in human T and natural killer (NK) cells by using freshly isolated lymphocytes enriched for T and NK cells as starting material. After growing these lymphocytes for 5 days in the presence of interleukin (IL)–2, we isolated and characterized several antibacterial peptides/proteins from the supernatant—α-defensins (HNP 1-3), LL-37, lysozyme, and a fragment of histone H2B—although other active components were also present. We then used reverse transcriptase–polymerase chain reaction to search for expression of the gene coding for LL-37 in several B-cell lines, γδ T-cell lines, NK clones, and one monocytic cell line, with positive results, but found no expression in several αβ T-cell lines. The α-defensins (HNP 1-3) were also found to be expressed in several of these cell lines. To confirm the presence of these antibacterial peptides in lymphocytes, we localized them to NK, γδ T cells, B cells, and monocytes/macrophages by using double-staining immunohistochemical analysis of freshly isolated lymphocytes. We also found that primary cultures of lymphocytes transcribe and secrete LL-37 and that these processes are affected by IL-6 and interferon-γ. In addition, we demonstrated that LL-37 has chemotactic activity for polymorphonuclear leukocytes and CD4 T lymphocytes, whereas others have shown chemotactic activity for human α-defensins (HNP 1-2). These findings suggest that microbicidal peptides are effector molecules of lymphocytes and that antibacterial activity previously shown to be derived from T and NK cells may be partly mediated by the antibacterial peptides LL-37 and HNP 1-3.
Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells
Authors: Brossart Peter , Wirths Stefan , Stuhler Gernot , Reichardt Volker L. , Kanz Lothar , Brugger Wolfram 
Published: October 2019

AbstractVaccination of patients with cancer using dendritic cells (DCs) was shown to be effective for B-cell lymphoma and malignant melanoma. Here we provide evidence that patients with advanced breast and ovarian cancer can be efficiently vaccinated with autologous DCs pulsed with HER-2/neu– or MUC1-derived peptides. Ten patients were included in this pilot study. The DC vaccinations were well tolerated with no side effects. In 5 of 10 patients, peptide-specific cytotoxic T lymphocytes (CTLs) could be detected in the peripheral blood using both intracellular IFN-γ staining and 51Cr-release assays. The major CTL response in vivo was induced with the HER-2/neu–derived E75 and the MUC1-derived M1.2 peptide, which lasted for more than 6 months, suggesting that these peptides might be immunodominant. In addition, in one patient vaccinated with the MUC1-derived peptides, CEA- and MAGE-3 peptide-specific T-cell responses were detected after several vaccinations. In a second patient immunized with the HER-2/neu peptides, MUC1-specific T lymphocytes were induced after 7 immunizations, suggesting that antigen spreading in vivo might occur after successful immunization with a single tumor antigen. Our results show that vaccination of DCs pulsed with a single tumor antigen may induce immunologic responses in patients with breast and ovarian cancer. This study may be relevant to the design of future clinical trials of other peptide-based vaccines.
Molecular single-cell analysis of the clonal relationship of small Epstein-Barr virus–infected cells and Epstein-Barr virus–harboring Hodgkin and Reed/Sternberg cells in Hodgkin disease
Authors: Spieker Tilmann , Kurth Julia , Küppers Ralf , Rajewsky Klaus , Bräuninger Andreas , Hansmann Martin-Leo 
Published: October 2019

Abstract
Epstein-Barr virus (EBV) can be detected in the tumor cells of approximately 40% of cases of classical Hodgkin disease (cHD). Clonality studies suggest that infection of the neoplastic Hodgkin and Reed/Sternberg (HRS) cells occurs before tumor clone expansion. In EBV-positive cases, variable numbers of EBER-positive small B cells are sometimes also observed that immunohistologically differ from the neoplastic cells by lack of CD30 and latent membrane protein 1 expression. To analyze the clonal relationship between these EBV+ cells and the HRS cells, single EBV-infected CD30− B cells, as well as HRS cells from 3 cases of EBV-positive cHD were micromanipulated, their immunoglobulin gene rearrangements amplified and then compared with each other. In 2 cases, all small EBV-infected cells were clonally unrelated to the HRS cells. In a third case, 2 of 29 small CD30− cells were found to carry HRS cell-specific rearrangements. Thus, small CD30−EBV-infected B cells in cHD belong to the HRS tumor clone rarely, if at all. In all cases, small clones unrelated to the HRS cell clones were identified among the small EBV+ CD30− cells. The vast majority of small EBV+ CD30− B cells was found to carry somatically mutated V region genes, indicating that in lymph nodes of patients with HD, like in the peripheral blood of healthy individuals, EBV persists in memory B cells.
Involvement of CD44-hyaluronan interaction in malignant cell homing and fibronectin synthesis in hairy cell leukemia
Authors: Aziz Khalil A. , Till Kathleen J. , Zuzel Mirko , Cawley John C. 
Published: October 2019

AbstractThe tissue homing of malignant hematic cells has both diagnostic and pathogenetic importance. Although such homing is incompletely understood, it generally involves cell adhesion and migration mediated by a number of adhesion receptors and cytokines. In this article, the potential importance of hyaluronan (HA) is examined for the tissue homing of hairy cells (HCs) in hairy cell leukemia (HCL). It is shown that HCs readily adhere to, and spontaneously move on, HA-coated surfaces using CD44. This indicates that activated CD44 and spontaneous movement on HA form part of the intrinsically activated phenotype of HCs. Interleukin-8 (IL-8) inhibited HC movement on HA, and this cell arrest was accompanied by increased actin polymerization and a more pronounced association of CD44 with the cytoskeleton. All of these findings are in sharp contrast to our previous observations with chronic lymphocytic leukemia cells, which are nonmotile on HA, but in response to IL-8 become polarized and motile using the receptor for HA-mediated motility rather than their apparently inactive CD44. Immunohistochemical examination of HCL tissues showed the ubiquitous presence of IL-8 and the prominence of HA in bone marrow stroma and hepatic portal tracts. This suggests that CD44-HA interactions are important in HC homing to these sites, but not to splenic red pulp or hepatic sinusoids, where HA is largely absent. Moreover, engagement of CD44 on HCs stimulates fibronectin synthesis, an observation that is likely to be relevant to the restriction of fibrosis in the disease to HC-infiltrated areas containing HA.
The Fanconi anemia proteins FANCA and FANCG stabilize each other and promote the nuclear accumulation of the Fanconi anemia complex
Authors: Garcia-Higuera Irene , Kuang Yanan , Denham Jessica , D'Andrea Alan D. 
Published: October 2019

Abstract
Fanconi anemia (FA) is an autosomal recessive cancer susceptibility syndrome with 8 complementation groups. Four of the FA genes have been cloned, and at least 3 of the encoded proteins, FANCA, FANCC, and FANCG/XRCC9, interact in a multisubunit protein complex. The FANCG protein binds directly to the amino terminal nuclear localization sequence (NLS) of FANCA, suggesting that FANCG plays a role in regulating FANCA nuclear accumulation. In the current study the functional consequences of FANCG/FANCA binding were examined. Correction of an FA-G cell line with the FANCG complementary DNA (cDNA) resulted in FANCA/FANCG binding, prolongation of the cellular half-life of FANCA, and an increase in the nuclear accumulation of the FA protein complex. Similar results were obtained upon correction of an FA-A cell line, with a reciprocal increase in the half-life of FANCG. Patient-derived mutant forms of FANCA, containing an intact NLS sequence but point mutations in the carboxy-terminal leucine zipper region, bound FANCG in the cytoplasm. The mutant forms failed to translocate to the nucleus of transduced cells, thereby suggesting a model of coordinated binding and nuclear translocation. These results demonstrate that the FANCA/FANCG interaction is required to maintain the cellular levels of both proteins. Moreover, at least one function of FANCG and FANCA is to regulate the nuclear accumulation of the FA protein complex. Failure to accumulate the nuclear FA protein complex results in the characteristic spectrum of clinical and cellular abnormalities observed in FA.
Regulation of hemoglobin synthesis and proliferation of differentiating erythroid cells by heme-regulated eIF-2α kinase
Authors: Crosby John S. , Chefalo Peter J. , Yeh Irene , Ying Shong , London Irving M. , Leboulch Philippe , Chen Jane-Jane 
Published: October 2019

AbstractProtein synthesis in reticulocytes depends on the availability of heme. In heme deficiency, inhibition of protein synthesis correlates with the activation of heme-regulated eIF-2α kinase (HRI), which blocks the initiation of protein synthesis by phosphorylating eIF-2α. HRI is a hemoprotein with 2 distinct heme-binding domains. Heme negatively regulates HRI activity by binding directly to HRI. To further study the physiological function of HRI, the wild-type (Wt) HRI and dominant-negative inactive mutants of HRI were expressed by retrovirus-mediated transfer in both non-erythroid NIH 3T3 and mouse erythroleukemic (MEL) cells. Expression of Wt HRI in 3T3 cells resulted in the inhibition of protein synthesis, a loss of proliferation, and eventually cell death. Expression of the inactive HRI mutants had no apparent effect on the growth characteristics or morphology of NIH 3T3 cells. In contrast, expression of 3 dominant-negative inactive mutants of HRI in MEL cells resulted in increased hemoglobin production and increased proliferative capacity of these cells upon dimethyl-sulfoxide induction of erythroid differentiation. These results directly demonstrate the importance of HRI in the regulation of protein synthesis in immature erythroid cells and suggest a role of HRI in the regulation of the numbers of matured erythroid cells.
Apoptosis in megaloblastic anemia occurs during DNA synthesis by a p53-independent, nucleoside-reversible mechanism
Authors: Koury Mark J. , Price James O. , Hicks Geoffrey G. 
Published: October 2019

AbstractDeficiency of folate or vitamin B12 (cobalamin) causes megaloblastic anemia, a disease characterized by pancytopenia due to the excessive apoptosis of hematopoietic progenitor cells. Clinical and experimental studies of megaloblastic anemia have demonstrated an impairment of DNA synthesis and repair in hematopoietic cells that is manifested by an increased percentage of cells in the DNA synthesis phase (S phase) of the cell cycle, compared with normal hematopoietic cells. Both folate and cobalamin are required for normal de novo synthesis of thymidylate and purines. However, previous studies of impaired DNA synthesis and repair in megaloblastic anemia have concerned mainly the decreased intracellular levels of thymidylate and its effects on nucleotide pools and misincorporation of uracil into DNA. An in vitro model of folate-deficient erythropoiesis was used to study the relationship between the S-phase accumulation and apoptosis in megaloblastic anemia. The results indicate that folate-deficient erythroblasts accumulate in and undergo apoptosis in the S phase when compared with control erythroblasts. Both the S-phase accumulation and the apoptosis were induced by folate deficiency in erythroblasts fromp53 null mice. The complete reversal of the S-phase accumulation and apoptosis in folate-deficient erythroblasts required the exogenous provision of specific purines or purine nucleosides as well as thymidine. These results indicate that decreased de novo synthesis of purines plays as important a role as decreased de novo synthesis of thymidylate in the pathogenesis of megaloblastic anemia.
Assessment of bone marrow stem cell reserve and function and stromal cell function in patients with autoimmune cytopenias
Authors: Papadaki Helen A. , Gibson Frances M. , Rizzo Sian , Gordon-Smith Edward C. , Marsh Judith C. W. 
Published: October 2019

Abstract
To investigate whether bone marrow (BM) stem cell compartment and/or BM microenvironment are affected by the immune insult in autoimmune cytopenias (AICs), BM stem cell reserve and function and BM stromal function were studied in 15 AIC patients. Stem cells were evaluated by means of flow cytometry, clonogenic progenitor cell assays, long-term BM cultures (LTBMCs), and limiting dilution assay for quantification of long-term–culture initiating cells (LTC-ICs). Stromal cell function was assessed with the use of preformed irradiated LTBMCs from patients and normal controls, recharged with normal CD34+ cells. AIC patients exhibited a high number of CD34+, CD34+/CD38+, and CD34+/CD38− cells; high frequency of granulocyte-macrophage colony forming units in the BM mononuclear cell fraction; high colony recovery in LTBMCs; and normal LTC-IC frequency. Patient BM stromal layers displayed normal hematopoietic-supporting capacity and increased production of granulocyte-colony stimulating factor. Data from this study support the concept that AIC patients with severe, resistant disease might be appropriate candidates for autologous stem cell transplantation.
Low B-cell and monocyte counts on day 80 are associated with high infection rates between days 100 and 365 after allogeneic marrow transplantation
Authors: Storek Jan , Espino German , Dawson Monja A. , Storer Barry , Flowers Mary E. D. , Maloney David G. 
Published: October 2019

AbstractTo ascertain which mononuclear cell subset deficiency plays a role in the marrow transplant recipient's susceptibility to infections, mononuclear cell subset counts were prospectively determined in 108 patients on day 80. Infections occurring between day 100 and 365 were recorded by an investigator blinded to the subset counts. In univariate analyses, the counts of the following subsets showed a significant inverse correlation with infection rates: total B cells, IgD+ B cells, IgD− B cells, total CD4 T cells, CD28+ CD4 T cells, CD28− CD4 T cells, CD45RAlow/− CD4 T cells and monocytes. In multivariate analyses, the counts of the following subsets remained significantly inversely correlated with the infection rates: total B cells (P = .0004) and monocytes (P = .009). CD28− CD8 T-cell counts showed no correlation with infection rates. In conclusion, the susceptibility of patients to infections late posttransplant may be due in part to the slow reconstitution of B cells and monocytes.
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

Abstract

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

AbstractBackgroundSubacromial 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.MethodsSystematic 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.ResultsSixty-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.ConclusionsEvidence 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 registrationPROSPEROCRD42019126917, 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

Abstract

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

AbstractBackgroundAberrant 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.MethodsIn 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.ResultsWe 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.ConclusionsThese 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